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  • 1. Almandoz-Gil, Leire
    et al.
    Welander, Hedvig
    Ihse, Elisabet
    Khoonsari, Payam Emami
    Musunuri, Sravani
    Lendel, Christofer
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Applied Physical Chemistry.
    Sigvardson, Jessica
    Karlsson, Mikael
    Ingelsson, Martin
    Kultima, Kim
    Bergstrom, Joakim
    Low molar excess of 4-oxo-2-nonenal and 4-hydroxy-2-nonenal promote oligomerization of alpha-synuclein through different pathways2017In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 110, p. 421-431Article in journal (Refereed)
    Abstract [en]

    Aggregated alpha-synuclein is the main component of Lewy bodies, intraneuronal inclusions found in brains with Parkinson's disease and dementia with Lewy bodies. A body of evidence implicates oxidative stress in the pathogenesis of these diseases. For example, a large excess (30: 1, aldehyde: protein) of the lipid peroxidation end products 4-oxo-2-nonenal (ONE) or 4-hydroxy-2-nonenal (HNE) can induce alpha-synuclein oligomer formation. The objective of the study was to investigate the effect of these reactive aldehydes on alpha-synuclein at a lower molar excess (3: 1) at both physiological (7.4) and acidic (5.4) pH. As observed by size-exclusion chromatography, ONE rapidly induced the formation of alpha-synuclein oligomers at both pH values, but the effect was less pronounced under the acidic condition. In contrast, only a small proportion of alpha-synuclein oligomers were formed with low excess HNE-treatment at physiological pH and no oligomers at all under the acidic condition. With prolonged incubation times (up to 96 h), more alpha-synuclein was oligomerized at physiological pH for both ONE and HNE. As determined by Western blot, ONE-oligomers were more SDS-stable and to a higher-degree cross-linked as compared to the HNE-induced oligomers. However, as shown by their greater sensitivity to proteinase K treatment, ONE-oligomers, exhibited a less compact structure than HNE-oligomers. As indicated by mass spectrometry, ONE modified most Lys residues, whereas HNE primarily modified the His50 residue and fewer Lys residues, albeit to a higher degree than ONE. Taken together, our data show that the aldehydes ONE and HNE can modify alpha-synuclein and induce oligomerization, even at low molar excess, but to a higher degree at physiological pH and seemingly through different pathways.

  • 2.
    Almandoz-Gil, Leire
    et al.
    Uppsala Univ, Dept Publ Hlth & Caring Sci, Mol Geriatr, SE-75185 Uppsala, Sweden..
    Welander, Hedvig
    Uppsala Univ, Dept Publ Hlth & Caring Sci, Mol Geriatr, SE-75185 Uppsala, Sweden..
    Ihse, Elisabeth
    Uppsala Univ, Dept Publ Hlth & Caring Sci, Mol Geriatr, SE-75185 Uppsala, Sweden..
    Khoonsari, Payam Emami
    Uppsala Univ, Dept Med Sci, SE-75185 Uppsala, Sweden..
    Musunuri, Sravani
    Uppsala Univ, Dept Med Sci, SE-75185 Uppsala, Sweden..
    Lendel, Christofer
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry.
    Sigvardson, Jessica
    BioArctic AB, Warfvinges Vag 35, SE-11251 Stockholm, Sweden..
    Karlsson, Mikael
    Uppsala Univ, Dept Engn Sci, SE-75121 Uppsala, Sweden..
    Ingelsson, Martin
    Uppsala Univ, Dept Publ Hlth & Caring Sci, Mol Geriatr, SE-75185 Uppsala, Sweden..
    Kultima, Kim
    Uppsala Univ, Dept Med Sci, SE-75185 Uppsala, Sweden..
    Bergstrom, Joakim
    Uppsala Univ, Dept Publ Hlth & Caring Sci, Mol Geriatr, SE-75185 Uppsala, Sweden..
    Low molar excess of 4-oxo-2-nonenal and 4-hydroxy-2-nonenal promote oligomerization of alpha-synuclein through different pathways (vol 110, pg 421, 2017)2018In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 117, p. 258-258Article in journal (Refereed)
  • 3.
    Atapour, Masoud
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry, Surface and Corrosion Science.
    Wei, Zheng
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry, Surface and Corrosion Science.
    Chaudhary, Himanshu
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry, Applied Physical Chemistry.
    Lendel, Christofer
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry, Applied Physical Chemistry.
    Odnevall Wallinder, Inger
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry, Surface and Corrosion Science.
    Hedberg, Yolanda
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry, Surface and Corrosion Science.
    Metal release from stainless steel 316L in whey protein - And simulated milk solutions under static and stirring conditions2019In: Food Control, ISSN 0956-7135, E-ISSN 1873-7129, Vol. 101, p. 163-172Article in journal (Refereed)
    Abstract [en]

    Stainless steel is an important transport and processing contact material for bovine milk and dairy products. Release (migration) of metals, ions, complexes or wear debris/particles, and metal-induced protein aggregation in such environments are hence important to consider both from a corrosion and food safety perspective. This study aims on investigating the release of iron (Fe), chromium (Cr), and nickel (Ni) from AISI 316L stainless steel in contact with whey protein solutions relevant for protein drinks, and on how the whey proteins are influenced by stirring with a magnetic stir bar and metal release. Mechanistic insight is gained by parallel investigations of metal release from two reference non-protein containing solutions, a metal-complexing (citrate-containing) simulated milk solution (SMS) and a low complexing phosphate buffered saline solution (PBS). All immersion exposures were conducted at pH 6.8 for 0.5, 4, 24 and 48 hat room temperature at static and stirring conditions. All solutions and samples were investigated using different chemical, spectroscopic, microscopic, and electrochemical methods. Significantly higher amounts of Fe, Cr, and Ni were released into the whey protein solution (80 g/L) as compared to SMS and PBS. Strong enrichment of Cr in the surface oxide and reduction of the surface oxide thickness were associated with a higher amount of Ni release in the metal-complexing solutions (SMS and whey protein) compared with PBS. Stirring conditions resulted in higher amounts of metal release, enrichment of Cr in the surface oxide, and clear signs of wear of the 316L surface in all solutions compared to static conditions. The wear mechanism in the whey protein solution was different as compared to corresponding processes in SMS and PBS, involving an etching-like process and larger-sized wear debris. Electrochemical measurements at static conditions confirmed observed differences between the solutions, with the lowest corrosion resistance observed for coupons exposed in the whey protein solution, followed by SMS and PBS. Released metals in solution from the 316L coupons in contact with the whey protein solution resulted in enhanced rates of protein aggregation and precipitation of protein aggregates from solution. Further studies should be made to investigate other relevant test conditions and assess toxicological risks.

  • 4. Cai, Yixiao
    et al.
    Lendel, Christofer
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Applied Physical Chemistry.
    Österlund, Lars
    Kasrayan, Alex
    Lannfelt, Lars
    Ingelsson, Martin
    Nikolajeff, Fredrik
    Karlsson, Mikael
    Bergstrom, Joakim
    Changes in secondary structure of alpha-synuclein during oligomerization induced by reactive aldehydes2015In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 464, no 1, p. 336-341Article in journal (Refereed)
    Abstract [en]

    The oxidative stress-related reactive aldehydes 4-hydroxy-2-nonenal (HNE) and 4-oxo-2-nonenal (ONE) have been shown to promote formation of alpha-synuclein oligomers in vitro. However, the changes in secondary structure of alpha-synuclein and the kinetics of the oligomerization process are not known and were the focus of this study. Size exclusion chromatography showed that after 1 h of incubation, HNE induced the formation of an oligomeric alpha-synuclein peak with a molecular weight of about similar to 2000 kDa, which coincided with a decreasing similar to 50 kDa monomeric peak. With prolonged incubation (up to 24 h) the oligomeric peak became the dominating molecular species. In contrast, in the presence of ONE, a similar to 2000 oligomeric peak was exclusively observed after 15 min of incubation and this peak remained constant with prolonged incubation. Western blot analysis of HNE-induced alpha-synuclein oligomers showed the presence of monomers (15 kDa), SDS-resistant low molecular (30-160 kDa) and high molecular weight oligomers (>= 260 kDa), indicating that the oligomers consisted of both covalent and non-covalent protein. In contrast, ONE-induced alpha-synuclein oligomers only migrated as covalent cross-linked high molecular-weight material (>= 300 kDa). Both circular dichroism (CD) and Attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy showed that the formation of HNE- and ONE-induced oligomers coincided with a spectral change from random coil to beta-sheet. However, ONE-induced alpha-synuclein oligomers exhibited a slightly higher degree of beta-sheet. Taken together, our results indicate that both HNE and ONE induce a change from random coil to beta-sheet structure that coincides with the formation of alpha-synuclein oligomers; albeit through different kinetic pathways depending on the degree of cross-linking. (C) 2015 Elsevier Inc. All rights reserved.

  • 5.
    Chaudhary, Himanshu
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry, Applied Physical Chemistry.
    Ferreira Fernandes, Ricardo M.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry, Applied Physical Chemistry. Centro de Investigação em Química, Department of Chemistry and Biochemistry, Faculty of Science, University of Porto, Rua do Campo Alegre, s/n, Porto, P-4169-007, Portugal.
    Gowda, Vasantha
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry, Applied Physical Chemistry.
    Claessens, Mirelle M. A. E.
    Furo, Istvan
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry, Applied Physical Chemistry.
    Lendel, Christofer
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry, Applied Physical Chemistry.
    Intrinsically disordered protein as carbon nanotube dispersant: How dynamic interactions lead to excellent colloidal stability2019In: Journal of Colloid and Interface Science, ISSN 0021-9797, E-ISSN 1095-7103, Vol. 556, p. 172-179Article in journal (Refereed)
    Abstract [en]

    The rich pool of protein conformations combined with the dimensions and properties of carbon nanotubes create new possibilities in functional materials and nanomedicine. Here, the intrinsically disordered protein α-synuclein is explored as a dispersant of single-walled carbon nanotubes (SWNTs) in water. We use a range of spectroscopic methods to quantify the amount of dispersed SWNT and to elucidate the binding mode of α-synuclein to SWNT. The dispersion ability of α-synuclein is good even with mild sonication and the obtained dispersion is very stable over time. The whole polypeptide chain is involved in the interaction accompanied by a fraction of the chain changing into a helical structure upon binding. Similar to other dispersants, we observe that only a small fraction (15–20%) of α-synuclein is adsorbed on the SWNT surface with an average residence time below 10 ms

  • 6.
    Dincbas-Renqvist, Vildan
    et al.
    KTH, Superseded Departments, Biotechnology.
    Lendel, Christofer
    KTH, School of Biotechnology (BIO).
    Dogan, Jakob
    KTH, Superseded Departments, Biotechnology.
    Wahlberg, Elisabet
    KTH, Superseded Departments, Biotechnology.
    Härd, Torleif
    Göteborgs Universitet.
    Thermodynamics of folding, stabilization, and binding in an engineered protein-protein complex2004In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 126, no 36, p. 11220-11230Article in journal (Refereed)
    Abstract [en]

    We analyzed the thermodynamics of a complex protein-protein binding interaction using the (engineered) Z(SPA-1) affibody and it's Z domain binding partner as a model. Free Z(SPA-1) exists in an equilibrium between a molten-globule-like (MG) state and a completely unfolded state, wheras a well-ordered structure is observed in the Z:Z(SPA-1) complex. The thermodynamics of the MG state unfolding equilibrium can be separated from the thermodynamics of binding and stabilization by combined analysis of isothermal titration calorimetry data and a separate van't Hoff analysis of thermal unfolding. We find that (i) the unfolding equilibrium of free Z(SPA-1) has only a small influence on effective binding affinity, that (ii) the Z:Z(SPA-1) interface is inconspicuous and structure-based energetics calculations suggest that it should be capable of supporting strong binding, but that (iii) the conformational stabilization of the MG state to a well-ordered structure in the Z:Z(SPA-1) complex is associated with a large change in conformational entropy that opposes binding.

  • 7.
    Dogan, Jakob
    et al.
    KTH, School of Biotechnology (BIO).
    Lendel, Christofer
    KTH, School of Biotechnology (BIO).
    Härd, Torleif
    Göteborgs Universitet.
    NMR assignments of the free and bound-state protein components of an anti-idiotypic affibody complex2006In: Journal of Biomolecular NMR, ISSN 0925-2738, E-ISSN 1573-5001, Vol. 36, p. (Electronic publication ahead of print Feb. 6; doi:10.1007/s10858-005-5350-8)Article in journal (Refereed)
  • 8.
    Dogan, Jakob
    et al.
    KTH, School of Biotechnology (BIO), Molecular Biotechnology.
    Lendel, Christofer
    KTH, School of Biotechnology (BIO), Molecular Biotechnology.
    Härd, Torleif
    Thermodynamics of folding and binding in an affibody:affibody complex2006In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 359, no 5, p. 1305-1315Article in journal (Refereed)
    Abstract [en]

    Affibody binding proteins are selected from phage-displayed libraries of variants of the 58 residue Z domain. Z(Taq) is an affibody originally selected as a binder to Taq DNA polymerase. The anti-Z(Taq) affibody was selected as a binder to Z(Taq) and the Z(Taq):anti-Z(Taq) complex is formed with a dissociation constant K-d = 0.1 mu M. We have determined the structure of the Z(Taq):anti-Z(Taq) complex as well as the free state structures of Z(Taq) and anti-Z(Taq) using NMR. Here we complement the structural data with thermodynamic studies of Z(Taq) and anti-Z(Taq) folding and complex formation. Both affibody proteins show cooperative two-state thermal denaturation at melting temperatures T-M similar to 56 degrees C. Z(Taq):anti-Z(Taq) complex formation at 25 degrees C in 50 mM NaCl and 20 mM phosphate buffer (pH 6.4) is enthalpy driven with Delta H degrees(bind) = -9.0(+/- 0.1) kcal mol(-1). The heat capacity change Delta C-P degrees,(bind) = -0.43(+/- 0.01) kcal mol(-1) K-1 is in accordance with the predominantly non-polar character of the binding surface, as judged from calculations based on changes in accessible surface areas. A further dissection of the small binding entropy at 25 degrees C (-T Delta S degrees(bind) = -0.6(+/- 0.1) kcal mol(-1)) suggests that a favourable desolvation of non-polar surface is almost completely balanced by unfavourable conformational entropy changes and loss of rotational and translational entropy. Such effects can therefore be limiting for strong binding also when interacting protein components are stable and homogeneously folded. The combined structure and thermodynamics data suggest that protein properties are not likely to be a serious limitation for the development of engineered binding proteins based on the Z domain.

  • 9. Dubnovitsky, Anatoly
    et al.
    Sandberg, Anders
    Rahman, M Mahafuzur
    Benilova, Iryna
    Lendel, Christofer
    Härd, Torleif
    Amyloid-β protofibrils: size, morphology and synaptotoxicity of an engineered mimic.2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 7, article id e66101Article in journal (Refereed)
    Abstract [en]

    Structural and biochemical studies of the aggregation of the amyloid-β peptide (Aβ) are important to understand the mechanisms of Alzheimer's disease, but research is complicated by aggregate inhomogeneity and instability. We previously engineered a hairpin form of Aβ called Aβcc, which forms stable protofibrils that do not convert into amyloid fibrils. Here we provide a detailed characterization of Aβ42cc protofibrils. Like wild type Aβ they appear as smooth rod-like particles with a diameter of 3.1 (±0.2) nm and typical lengths in the range 60 to 220 nm when observed by atomic force microscopy. Non-perturbing analytical ultracentrifugation and nanoparticle tracking analyses are consistent with such rod-like protofibrils. Aβ42cc protofibrils bind the ANS dye indicating that they, like other toxic protein aggregates, expose hydrophobic surface. Assays with the OC/A11 pair of oligomer specific antibodies put Aβ42cc protofibrils into the same class of species as fibrillar oligomers of wild type Aβ. Aβ42cc protofibrils may be used to extract binding proteins in biological fluids and apolipoprotein E is readily detected as a binder in human serum. Finally, Aβ42cc protofibrils act to attenuate spontaneous synaptic activity in mouse hippocampal neurons. The experiments indicate considerable structural and chemical similarities between protofibrils formed by Aβ42cc and aggregates of wild type Aβ42. We suggest that Aβ42cc protofibrils may be used in research and applications that require stable preparations of protofibrillar Aβ.

  • 10.
    Hedberg, Yolanda
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry, Surface and Corrosion Science.
    Dobryden, Illia
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry, Surface and Corrosion Science.
    Chaudhary, Himanshu
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry, Applied Physical Chemistry.
    Wei, Zheng
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry, Surface and Corrosion Science.
    Claesson, Per M.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry, Surface and Corrosion Science.
    Lendel, Christofer
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry, Applied Physical Chemistry.
    Synergistic effects of metal-induced aggregation of human serum albumin2019In: Colloids and Surfaces B: Biointerfaces, ISSN 0927-7765, E-ISSN 1873-4367, Vol. 173, p. 751-758Article in journal (Refereed)
    Abstract [en]

    Exposure to cobalt (Co), chromium (Cr), and nickel (Ni) occurs often via skin contact and from different dental and orthopedic implants. The metal ions bind to proteins, which may induce structural changes and aggregation, with different medical consequences. We investigated human serum albumin (HSA) aggregation in the presence of Co-II, Cr-III, and/or Ni-II ions and/or their nanoparticle precipitates by using scattering, spectroscopic, and imaging techniques, at simulated physiological conditions (phosphate buffered saline - PBS, pH 7.3) using metal salts that did not affect the pH, and at HSA:metal molar ratios of up to 1:8. Co ions formed some solid nano particles in PBS at the investigated conditions, as determined by nanoparticle tracking analysis, but the Cr-III anions and Ni-II ions remained fully soluble. It was found that all metal ions induced HSA aggregation, and this effect was significantly enhanced when a mixture of all three metal ions was present instead of any single type of ion. Thus, the metal ions induce aggregation synergistically. HSA aggregates formed linear structures on a mica surface in the presence of Cr-III ions. A clear tendency of aggregation and linearly aligned aggregates was seen in the presence of all three metal ions. Spectroscopic investigations indicated that the majority of the HSA molecules maintained their alpha helical secondary structure and conformation. This study highlights the importance of synergistic effects of metal ions and/or their precipitates on protein aggregation, which are highly relevant for implant materials and common exposures to metals.

  • 11. Härd, Torleif
    et al.
    Lendel, Christofer
    Inhibition of amyloid formation.2012In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 421, no 4-5, p. 441-65Article in journal (Refereed)
    Abstract [en]

    Amyloid is aggregated protein in the form of insoluble fibrils. Amyloid deposition in human tissue-amyloidosis-is associated with a number of diseases including all common dementias and type II diabetes. Considerable progress has been made to understand the mechanisms leading to amyloid formation. It is, however, not yet clear by which mechanisms amyloid and protein aggregates formed on the path to amyloid are cytotoxic. Strategies to prevent protein aggregation and amyloid formation are nevertheless, in many cases, promising and even successful. This review covers research on intervention of amyloidosis and highlights several examples of how inhibition of protein aggregation and amyloid formation has been achieved in practice. For instance, rational design can provide drugs that stabilize a native folded state of a protein, protein engineering can provide new binding proteins that sequester monomeric peptides from aggregation, small molecules and peptides can be designed to block aggregation or direct it into non-cytotoxic paths, and monoclonal antibodies have been developed for therapies towards neurodegenerative diseases based on inhibition of amyloid formation and clearance.

  • 12.
    Josefsson, Leila
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry, Applied Physical Chemistry.
    Cronhamn, Melker
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry.
    Ekman, Malin
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry.
    Widehammar, Hugo
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry.
    Emmer, Åsa
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry, Applied Physical Chemistry.
    Lendel, Christofer
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry, Applied Physical Chemistry.
    Structural basis for the formation of soy protein nanofibrils2019In: RSC Advances, ISSN 2046-2069, E-ISSN 2046-2069, Vol. 9, no 11, p. 6310-6319Article in journal (Refereed)
    Abstract [en]

    Amyloid-like protein nanofibrils (PNFs) can assemble from a range of different proteins including disease-associated proteins, functional amyloid proteins and several proteins for which the PNFs are neither related to disease nor function. We here examined the core building blocks of PNFs formed by soy proteins. Fibril formation at pH 2 and 90 degrees C is coupled to peptide hydrolysis which allows isolation of the PNF-forming peptides and identification of them by mass spectrometry. We found five peptides that constitute the main building blocks in soy PNFs, three of them from the protein b-conglycinin and two from the protein glycinin. The abilities of these peptides to form PNFs were addressed by amyloid prediction software and by PNF formation of the corresponding synthetic peptides. Analysis of the structural context in the native soy proteins revealed two structural motifs for the PNF-forming peptides: (i) so-called b-arches and (ii) helical segments involved in quaternary structure contacts. However, the results suggest that neither the native structural motifs nor the protein of origin defines the morphology of the PNFs formed from soy protein isolate.

  • 13.
    Kamada, Ayaka
    et al.
    Univ Tokyo, Dept Bioengn, Tokyo, Japan..
    Mittal, Nitesh
    KTH, School of Engineering Sciences (SCI), Mechanics.
    Söderberg, Daniel
    KTH, School of Engineering Sciences (SCI), Mechanics.
    Lendel, Christofer
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry, Applied Physical Chemistry.
    Lundell, Fredrik
    KTH, School of Engineering Sciences (SCI), Mechanics.
    Assembly mechanism of nanostructured whey protein filaments2016In: Abstracts of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 252Article in journal (Other academic)
  • 14.
    Kamada, Ayaka
    et al.
    KTH, School of Engineering Sciences (SCI), Mechanics. KTH, School of Engineering Sciences (SCI), Centres, Linné Flow Center, FLOW.
    Mittal, Nitesh
    KTH, School of Engineering Sciences (SCI), Mechanics. KTH, School of Chemical Science and Engineering (CHE), Centres, Wallenberg Wood Science Center. KTH, School of Engineering Sciences (SCI), Centres, Linné Flow Center, FLOW.
    Söderberg, L. Daniel
    KTH, School of Engineering Sciences (SCI), Mechanics. KTH, School of Engineering Sciences (SCI), Centres, Linné Flow Center, FLOW. KTH, School of Chemical Science and Engineering (CHE), Centres, Wallenberg Wood Science Center.
    Ingverud, Tobias
    KTH, School of Chemical Science and Engineering (CHE), Centres, Wallenberg Wood Science Center. KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology.
    Ohm, Wiebke
    Roth, Stephan V.
    KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology. Photon Science, Deutsches Elektronen-Synchrotron (DESY), D-22607 Hamburg, Germany.
    Lundell, Fredrik
    KTH, School of Chemical Science and Engineering (CHE), Centres, Wallenberg Wood Science Center. KTH, School of Engineering Sciences (SCI), Centres, Linné Flow Center, FLOW. KTH, School of Engineering Sciences (SCI), Mechanics.
    Lendel, Christofer
    KTH, School of Chemical Science and Engineering (CHE), Chemistry.
    Flow-assisted assembly of nanostructured protein microfibers2017In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, no 6, p. 1232-1237Article in journal (Refereed)
    Abstract [en]

    Some of the most remarkable materials in nature are made from proteins. The properties of these materials are closely connected to the hierarchical assembly of the protein building blocks. In this perspective, amyloid-like protein nanofibrils (PNFs) have emerged as a promising foundation for the synthesis of novel bio-based materials for a variety of applications. Whereas recent advances have revealed the molecular structure of PNFs, the mechanisms associated with fibril-fibril interactions and their assembly into macroscale structures remain largely unexplored. Here, we show that whey PNFs can be assembled into microfibers using a flow-focusing approach and without the addition of plasticizers or cross-linkers. Microfocus small-angle X-ray scattering allows us to monitor the fibril orientation in the microchannel and compare the assembly processes of PNFs of distinct morphologies. We find that the strongest fiber is obtained with a sufficient balance between ordered nanostructure and fibril entanglement. The results provide insights in the behavior of protein nanostructures under laminar flow conditions and their assembly mechanism into hierarchical macroscopic structures.

  • 15.
    Lendel, Christofer
    KTH, School of Biotechnology (BIO).
    Molecular principles of protein stability and protein-protein interactions2005Doctoral thesis, comprehensive summary (Other scientific)
    Abstract [en]

    Proteins with highly specific binding properties constitute the basis for many important applications in biotechnology and medicine. Immunoglobulins have so far been the obvious choice but recent advances in protein engineering have provided several novel constructs that indeed challenge antibodies. One class of such binding proteins is based on the 58 residues three-helix bundle Z domain from staphylococcal protein A (SPA). These so-called affibodies are selected from libraries containing Z domain variants with 13 randomised positions at the immunoglobulin Fc-binding surface. This thesis aims to describe the principles for molecular recognition in two protein-protein complexes involving affibody proteins. The first complex is formed by the ZSPA-1 affibody binding to its own ancestor, the Z domain (Kd ~1 μM). The second complex consists of two affibodies: ZTaq, originally selected to bind Taq DNA polymerase, and anti-ZTaq, an anti-idiotypic binder to ZTaq with a Kd ~0.1 μM. The basis for the study is the determination of the three-dimensional structures using NMR spectroscopy supported by biophysical characterization of the uncomplexed proteins and investigation of binding thermodynamics using isothermal titration calorimetry. The free ZSPA-1 affibody is a molten globule-like protein with reduced stability compared to the original scaffold. However, upon target binding it folds into a well-defined structure with an interface topology resembling that displayed by the immunoglobulin Fc fragment when bound to the Z domain. At the same time, structural rearrangements occur in the Z domain in a similar way as in the Fc-binding process. The complex interface buries 1632 Å2 total surface area and 10 out of 13 varied residues in ZSPA-1 are directly involved in inter-molecular contacts. Further characterization of the molten globule state of ZSPA-1 revealed a native-like overall structure with increased dynamics in the randomised regions (helices 1 and 2). These features were reduced when replacing some of the mutated residues with the corresponding wild-type Z domain residues. The nature of the free ZSPA-1 affects the thermodynamics of the complex formation. The contribution from the unfolding equilibrium of the molten globule was successfully separated from the binding thermodynamics. Further decomposition of the binding entropy suggests that the conformational entropy penalty associated with stabilizing the molten globule state of ZSPA-1 upon binding seriously reduces the binding affinity. The ZTaq:anti-ZTaq complex buries in total 1672 Å2 surface area and all varied positions in anti-ZTaq are directly involved in binding. The main differences between the Z:ZSPA-1 and the ZTaq:anti-ZTaq complexes are the relative subunit orientation and certain specific interactions. However, there are also similarities, such as the hydrophobic interface character and the role of certain key residues, which are also found in the SPA:Fc interaction. Structural rearrangements upon binding are also common features of these complexes. Even though neither ZTaq nor anti-ZTaq shows the molten globule behaviour seen for ZSPA-1, there are indications of dynamic events that might affect the binding affinity. This study provides not only a molecular basis for affibody-target recognition, but also contributions to the understanding of the mechanisms regulating protein stability and protein-protein interactions in general.

  • 16. Lendel, Christofer
    et al.
    Bjerring, Morten
    Dubnovitsky, Anatoly
    Kelly, Robert T
    Filippov, Andrei
    Antzutkin, Oleg N.
    Nielsen, Niels C.
    Härd, Torleif
    A hexameric peptide barrel as building block of amyloid-β protofibrils.2014In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 53, p. 12756-12760Article in journal (Refereed)
    Abstract [en]

    Oligomeric and protofibrillar aggregates formed by the amyloid-A beta peptide (A beta) are believed to be involved in the pathology of Alzheimer's disease. Central to Alzheimer pathology is also the fact that the longer A beta(42) peptide is more prone to aggregation than the more prevalent A beta(40). Detailed structural studies of A beta oligomers and protofibrils have been impeded by aggregate heterogeneity and instability. We previously engineered a variant of A beta that forms stable protofibrils and here we use solid-state NMR spectroscopy and molecular modeling to derive a structural model of these. NMR data are consistent with packing of residues 16 to 42 of A beta protomers into hexameric barrel-like oligomers within the protofibril. The core of the oligomers consists of all residues of the central and C-terminal hydrophobic regions of A beta, and hairpin loops extend from the core. The model accounts for why A beta(42) forms oligomers and protofibrils more easily than A beta(40).

  • 17.
    Lendel, Christofer
    et al.
    KTH, Superseded Departments, Biotechnology.
    Dincbas-Renqvist, Vildan
    KTH, Superseded Departments, Biotechnology.
    Flores, Alexander
    KTH, Superseded Departments, Biotechnology.
    Wahlberg, Elisabet
    KTH, Superseded Departments, Biotechnology.
    Dogan, Jakob
    KTH, Superseded Departments, Biotechnology.
    Nygren, Per-Åke
    KTH, Superseded Departments, Biotechnology.
    Härd, Torleif
    Biophysical characterization of ZSPA-1-A phage-display selected binder to protein A2004In: Protein Science, ISSN 0961-8368, E-ISSN 1469-896X, Vol. 13, no 8, p. 2078-2088Article in journal (Refereed)
    Abstract [en]

    Affibodies are a novel class of binding proteins selected from phagemid libraries of the Z domain from staphylococcal protein A. The Z(SPA-1) affibody was selected as a binder to protein A, and it binds the parental Z domain with micromolar affinity. In earlier work we determined the structure of the Z:Z(SPA-1) complex and noted that Z(SPA-1) in the free state exhibits several properties characteristic of a molten globule. Here we present a more detailed biophysical investigation of Z(SPA-1) and four Z(SPA-1) mutants with the objective to understand these properties. The characterization includes thermal and chemical denaturation profiles, ANS binding assays, size exclusion chromatography, isothermal titration calorimetry, and an investigation of structure and dynamics by NMR. The NMR characterization of Z(SPA-1) was facilitated by the finding that trimethylamine N-oxide (TMAO) stabilizes the molten globule conformation in favor of the fully unfolded state. All data taken together lead us to conclude the following: (1) The topology of the molten globule conformation of free Z(SPA-1) is similar to that of the fully folded structure in the Z-bound state; (2) the extensive mutations in helices 1 and 2 destabilize these without affecting the intrinsic stability of helix 3; (3) stabilization and reduced aggregation can be achieved by replacing mutated residues in Z(SPA-1) with the corresponding wild-type Z residues. This stabilization is better correlated to changes in helix propensity than to an expected increase in polar versus nonpolar surface area of the fully folded state.

  • 18.
    Lendel, Christofer
    et al.
    KTH, School of Biotechnology (BIO).
    Dogan, Jakob
    KTH, School of Biotechnology (BIO).
    Härd, Torleif
    Göteborgs Universitet.
    Structural basis for molecular recognition in an affibody:affibody complex2006In: Asia-Pacific Journal of Molecular Biology and Biotechnology, ISSN 0128-7451, Vol. 359, no 5, p. 1293-1304Article in journal (Refereed)
    Abstract [en]

    Affibody molecules constitute a class of engineered binding proteins based on the 58-residue three-helix bundle Z domain derived from staphylococcal protein A (SPA). Affibody proteins are selected as binders to target proteins by phage display of combinatorial libraries in which typically 13 side-chains on the surface of helices 1 and 2 in the Z domain have been randomized. The Z(Taq):anti-Z(Taq) affibody-affibody complex, consisting of Z(Taq), originally selected as a binder to Taq DNA polymerase, and anti-Z(Taq), selected as binder to Z(Taq), is formed with a dissociation constant K-d similar to 100 nM. We have determined high-precision solution structures of free Z(Taq) and anti-Z(Taq), and the Z(Taq):anti-Z(Taq) complex under identical experimental conditions (25 degrees C in 50 mM NaCl with 20 mM potassium phosphate buffer at pH 6.4). The complex is formed with helices 1 and 2 of anti-Z(Taq) in perpendicular contact with helices 1 and 2 of Z(Taq). The interaction surface is large (similar to 1670 angstrom(2)) and unusually non-polar (70 %) compared to other protein-protein complexes. It involves all varied residues on anti-Z(Taq), most corresponding (Taq DNA polymerase binding) side-chains on Z(Taq), and several additional side-chain and backbone contacts. Other notable features include a substantial rearrangement (induced fit) of aromatic side-chains in Z(Taq) upon binding, a close contact between glycine residues in the two subunits that might involve aliphatic glycine H alpha to backbone carbonyl hydrogen bonds, and four hydrogen bonds made by the two guanidinium (NH2)-H-eta groups of an arginine side-chain. Comparisons of the present structure with other data for affibody proteins and the Z domain suggest that intrinsic binding properties of the originating SPA surface might be inherited by the affibody binders. A thermodynamic characterization of Z(Taq) and anti-Z(Taq) is presented in an accompanying paper.

  • 19.
    Lendel, Christofer
    et al.
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Applied Physical Chemistry.
    Sparrman, Tobias
    Mayzel, Maxim
    Andersson, C. Evalena
    Karlsson, Goran
    Hard, Torleif
    Combined Solution- and Magic Angle Spinning NMR Reveals Regions of Distinct Dynamics in Amyloid beta Protofibrils2016In: CHEMISTRYSELECT, ISSN 2365-6549, Vol. 1, no 18, p. 5850-5853Article in journal (Refereed)
    Abstract [en]

    Solid-state magic angle spinning (MAS) NMR has emerged as an important tool for investigations of protein aggregates and amyloid fibrils, which are not accessible for solution NMR experiments. We recently presented a structural model for amyloid beta (A beta) protofibrils based on MAS-NMR data. The absence of resonances for the N-terminus of A beta in this dataset suggested that it might be disordered and more dynamic than the structural core. We here provide evidence for a distinct dynamic regime in the N-terminal part of the peptide and show that the structural characteristics of this region can be elucidated using C-13-detected solution NMR. The results shed more light on the structural properties of pre-fibrillar A beta species and demonstrate the potential of combining MAS and solution NMR experiments for the characterization of structure and dynamics of complex protein assemblies.

  • 20.
    Lendel, Christofer
    et al.
    KTH, Superseded Departments, Biotechnology.
    Wahlberg, Elisabet
    KTH, Superseded Departments, Biotechnology.
    Berglund, Helena
    KTH, Superseded Departments, Biotechnology.
    Eklund, Malin
    KTH, Superseded Departments, Biotechnology.
    Nygren, Per-Åke
    KTH, Superseded Departments, Biotechnology.
    Härd, Torleif
    KTH, Superseded Departments, Biotechnology.
    1H, 13C and 15N resonance assignments of an affibody-target complex2002In: Journal of Biomolecular NMR, ISSN 0925-2738, E-ISSN 1573-5001, Vol. 24, no 3, p. 271-272Article in journal (Refereed)
  • 21. Rahman, M. Mahafazur
    et al.
    Zetterberg, Henrik
    Lendel, Christofer
    Swedish University of Agricultural Sciences (SLU), Sweden .
    Hard, Torleif
    Binding of Human Proteins to Amyloid-beta Protofibrils2015In: ACS Chemical Biology, ISSN 1554-8929, E-ISSN 1554-8937, Vol. 10, no 3, p. 766-774Article in journal (Refereed)
    Abstract [en]

    The progressive neurodegeneration in Alzheimers disease is believed to be linked to the presence of prefibrillar aggregates of the amyloid-beta (A beta) peptide in the brain. The exact role of these aggregates in the disease pathology is, however, still an open question. Any mechanism by which oligomeric A beta may cause damage to neuronal cells must, in one way or another, involve interactions with other molecules. Here, we identify proteins in human serum and cerebrospinal fluid that bind to stable protofibrils formed by an engineered variant of A beta 42 (A beta(42CC)). We find that the protofibrils attract a substantial number of protein binding partners. Many of the 101 identified proteins are involved in lipid transport and metabolism, the complement system, or in hemostasis. Binding of representative proteins from all of these groups with micromolar affinity was confirmed using surface plasmon resonance. In addition, binding of apolipoprotein E to the protofibrils with nanomolar affinity was demonstrated. We also find that aggregation of A beta enhances protein binding, as lower amounts of proteins bind monomeric A beta. Proteins that bind to A beta protofibrils might contribute to biological effects in which these aggregates are involved. Our results therefore suggest that an improved understanding of the mechanisms by which A beta causes cytotoxicity and neurodegeneration might be gained from studies carried out in biologically relevant matrices in which A beta-binding proteins are present.

  • 22.
    Wahlberg, Elisabet
    et al.
    KTH, Superseded Departments, Biotechnology.
    Lendel, Christofer
    KTH, Superseded Departments, Biotechnology.
    Helgstrand, Magnus
    KTH, Superseded Departments, Biotechnology.
    Allard, Peter
    KTH, Superseded Departments, Biotechnology.
    Dincbas-Renqvist, Vildan
    KTH, Superseded Departments, Biotechnology.
    Hedqvist, Anders
    Berglund, Helena
    KTH, Superseded Departments, Biotechnology.
    Nygren, Per-Åke
    KTH, Superseded Departments, Biotechnology.
    Härd, Torleif
    KTH, Superseded Departments, Biotechnology.
    An affibody in complex with a target protein: Structure and coupled folding.2003In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 100, no 6, p. 3185-3190Article in journal (Refereed)
    Abstract [en]

    Combinatorial protein engineering provides powerful means for functional selection of novel binding proteins. One class of engineered binding proteins, denoted affibodies, is based on the three-helix scaffold of the Z domain derived from staphylococcal protein A. The Z(SPA-1) affibody has been selected from a phage-displayed library as a binder to protein A. Z(SPA-1) also binds with micromolar affinity to its own ancestor, the Z domain. We have characterized the Z(SPA-1) affibody in its uncomplexed state and determined the solution structure of a Z:Z(SPA-1) protein-protein complex. Uncomplexed Z(SPA-1) behaves as an aggregation-prone molten globule, but folding occurs on binding, and the original (Z) three-helix bundle scaffold is fully formed in the complex. The structural basis for selection and strong binding is a large interaction interface with tight steric and polar/nonpolar complementarity that directly involves 10 of 13 mutated amino acid residues on Z(SPA-1). We also note similarities in how the surface of the Z domain responds by induced fit to binding of Z(SPA-1) and Ig Fc, respectively, suggesting that the Z(SPA-1) affibody is capable of mimicking the morphology of the natural binding partner for the Z domain.

  • 23.
    Ye, Xinchen
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Fibre- and Polymer Technology.
    Hedenqvist, Mikael S.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Fibre- and Polymer Technology.
    Langton, Maud
    Lendel, Christofer
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry, Applied Physical Chemistry.
    On the role of peptide hydrolysis for fibrillation kinetics and amyloid fibril morphology2018In: RSC Advances, ISSN 2046-2069, E-ISSN 2046-2069, Vol. 8, no 13, p. 6915-6924Article in journal (Refereed)
    Abstract [en]

    Self-assembly of proteins into amyloid-like nanofibrils is not only a key event in several diseases, but such fibrils are also associated with intriguing biological function and constitute promising components for new biobased materials. The bovine whey protein beta-lactoglobulin has emerged as an important model protein for the development of such materials. We here report that peptide hydrolysis is the rate-determining step for fibrillation of beta-lactoglobulin in whey protein isolate. We also explore the observation that beta-lactoglobulin nanofibrils of distinct morphologies are obtained by simply changing the initial protein concentration. We find that the morphological switch is related to different nucleation mechanisms and that the two classes of nanofibrils are associated with variations of the peptide building blocks. Based on the results, we propose that the balance between protein concentration and the hydrolysis rate determines the structure of the formed nanofibrils.

  • 24.
    Ye, Xinchen
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Fibre- and Polymer Technology, Polymeric Materials.
    Junel, Kristina
    RISE Bioecon Innventia AB, Drottning Kristinas Vag 61, SE-11486 Stockholm, Sweden..
    Gallstedt, Mikael
    SIG Combibloc, Vasagatan 7, SE-11120 Stockholm, Sweden..
    Langton, Maud
    SLU Swedish Agr Univ, Dept Mol Sci, Box 7015, S-75007 Uppsala, Sweden..
    Wei, Xin-Feng
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Fibre- and Polymer Technology, Polymeric Materials.
    Lendel, Christofer
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry, Applied Physical Chemistry.
    Hedenqvist, Mikael S.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Fibre- and Polymer Technology, Polymeric Materials.
    Protein/Protein Nanocomposite Based on Whey Protein Nanofibrils in a Whey Protein Matrix2018In: ACS Sustainable Chemistry and Engineering, ISSN 2168-0485, Vol. 6, no 4, p. 5462-5469Article in journal (Refereed)
    Abstract [en]

    This article describes nanocomposite films with separately grown protein nanofibrils (PNFs) in a nonfibrillar protein matrix from the same protein starting material (whey). Tensile tests on the glycerol-plasticized films indicate an increased elastic modulus and a decreased extensibility with increasing content of PNFs, although the films are still ductile at the maximum PNF content (15 wt %). Infrared spectroscopy confirms that the strongly hydrogen-bonded beta-sheets in the PNFs are retained in the composites. The films appear with a PNF-induced undulated upper surface. It is shown that micrometer-scale spatial variations in the glycerol distribution are not the cause of these undulations. Instead, the undulations seem to be a feature of the PNF material itself. It was also shown that, apart from plasticizing the protein film, the presence of glycerol seemed to favor to some extent exfoliation of stacked beta-sheets in the proteins, as revealed by X-ray diffraction.

  • 25.
    Ye, Xinchen
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Fibre- and Polymer Technology.
    Lendel, Christofer
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry, Applied Physical Chemistry.
    Langton, Maud
    Olsson, Richard
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Fibre- and Polymer Technology, Polymeric Materials.
    Hedenqvist, Mikael S.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Fibre- and Polymer Technology, Polymeric Materials.
    Protein nanofibrils: Preparation, properties, and possible applications in industrial nanomaterials2019In: Industrial Applications of Nanomaterials, Elsevier, 2019, p. 29-63Chapter in book (Other academic)
    Abstract [en]

    This chapter deals with protein nanofibrils (PNFs), also referred to as amyloid fibrils. This is an emerging field in nanoscience and engineering. Sources for PNFs, ways of making these, including the mechanisms of the fibrillation process, and factors affecting the production process are presented here. Properties of the PNFs themselves as well as properties and preparation of PNF materials in the form of hydrogels, films, and fibers are also described. In this chapter, PNF-based nanocomposites and templates are also considered. Possible applications of PNFs are discussed and put in the perspective of future uses as, or in, industrial nanomaterials.

1 - 25 of 25
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