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  • 1.
    Farsi, Zohreh
    et al.
    Max Planck Inst Biophys Chem, Dept Neurobiol, Gottingen, Germany.;Max Delbruck Ctr Mol Med, Berlin Inst Med Syst Biol, Berlin, Germany..
    Gowrisankaran, Sindhuja
    Univ Med Ctr Gottingen, European Neurosci Inst, Synapt Vesicle Dynam Grp, Gottingen, Germany..
    Krunic, Matija
    Univ Med Ctr Gottingen, European Neurosci Inst, Synapt Vesicle Dynam Grp, Gottingen, Germany..
    Rammner, Burkhard
    Sciloop, Hamburg, Germany..
    Woehler, Andrew
    Max Delbruck Ctr Mol Med, Berlin Inst Med Syst Biol, Berlin, Germany..
    Lafer, Eileen M.
    Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem & Struct Biol, San Antonio, TX 78229 USA.;Univ Texas Hlth Sci Ctr San Antonio, Ctr Biomed Neurosci, San Antonio, TX 78229 USA..
    Mim, Carsten
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems.
    Jahn, Reinhard
    Max Planck Inst Biophys Chem, Dept Neurobiol, Gottingen, Germany..
    Milosevic, Ira
    Univ Med Ctr Gottingen, European Neurosci Inst, Synapt Vesicle Dynam Grp, Gottingen, Germany..
    Clathrin coat controls synaptic vesicle acidification by blocking vacuolar ATPase activity2018In: eLIFE, E-ISSN 2050-084X, Vol. 7, article id e32569Article in journal (Refereed)
    Abstract [en]

    Newly-formed synaptic vesicles (SVs) are rapidly acidified by vacuolar adenosine triphosphatases (vATPases), generating a proton electrochemical gradient that drives neurotransmitter loading. Clathrin-mediated endocytosis is needed for the formation of new SVs, yet it is unclear when endocytosed vesicles acidify and refill at the synapse. Here, we isolated clathrin-coated vesicles (CCVs) from mouse brain to measure their acidification directly at the single vesicle level. We observed that the ATP-induced acidification of CCVs was strikingly reduced in comparison to SVs. Remarkably, when the coat was removed from CCVs, uncoated vesicles regained ATP-dependent acidification, demonstrating that CCVs contain the functional vATPase, yet its function is inhibited by the clathrin coat. Considering the known structures of the vATPase and clathrin coat, we propose a model in which the formation of the coat surrounds the vATPase and blocks its activity. Such inhibition is likely fundamental for the proper timing of SV refilling.

  • 2. Kaucka, Marketa
    et al.
    Zikmund, Tomas
    Tesarova, Marketa
    Gyllborg, Daniel
    Hellander, Andreas
    Jaros, Josef
    Kaiser, Jozef
    Petersen, Julian
    Szarowska, Bara
    Newton, Phillip T.
    Dyachuk, Vyacheslav
    li, Lei
    Qian, Hong
    Johansson, Anne-Sofie
    Mishina, Yuji
    Currie, Joshua D.
    Tanaka, Elly M.
    Erickson, Alek
    Dudley, Andrew
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cellular Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Southam, Paul
    Coen, Enrico
    Chen, Min
    Weinstein, Lee S.
    Hampl, Ales
    Arenas, Ernest
    Chagin, Andrei S.
    Fried, Kaj
    Adameyko, Igor
    Oriented clonal cell dynamics enables accurate growth and shaping of vertebrate cartilage2017In: eLIFE, E-ISSN 2050-084X, Vol. 6, article id e25902Article in journal (Refereed)
    Abstract [en]

    Cartilaginous structures are at the core of embryo growth and shaping before the bone forms. Here we report a novel principle of vertebrate cartilage growth that is based on introducing transversally-oriented clones into pre-existing cartilage. This mechanism of growth uncouples the lateral expansion of curved cartilaginous sheets from the control of cartilage thickness, a process which might be the evolutionary mechanism underlying adaptations of facial shape. In rod-shaped cartilage structures (Meckel, ribs and skeletal elements in developing limbs), the transverse integration of clonal columns determines the well-defined diameter and resulting rod-like morphology. We were able to alter cartilage shape by experimentally manipulating clonal geometries. Using in silico modeling, we discovered that anisotropic proliferation might explain cartilage bending and groove formation at the macro-scale.

  • 3. Kimanius, Dari
    et al.
    Forsberg, Bjorn O.
    Scheres, Sjors H. W.
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, SeRC - Swedish e-Science Research Centre. Stockholm University, Sweden.
    Accelerated cryo-EM structure determination with parallelisation using GPUs in RELION-22016In: eLIFE, E-ISSN 2050-084X, Vol. 5, article id e18722Article in journal (Refereed)
    Abstract [en]

    By reaching near-atomic resolution for a wide range of specimens, single-particle cryo-EM structure determination is transforming structural biology. However, the necessary calculations come at large computational costs, which has introduced a bottleneck that is currently limiting throughput and the development of new methods. Here, we present an implementation of the RELION image processing software that uses graphics processors (GPUs) to address the most computationally intensive steps of its cryo-EM structure determination workflow. Both image classification and high-resolution refinement have been accelerated more than an order-of-magnitude, and template-based particle selection has been accelerated well over two orders-of-magnitude on desktop hardware. Memory requirements on GPUs have been reduced to fit widely available hardware, and we show that the use of single precision arithmetic does not adversely affect results. This enables high-resolution cryo-EM structure determination in a matter of days on a single workstation.

  • 4. Ly, T.
    et al.
    Whigham, A.
    Clarke, R.
    Brenes-Murillo, A. J.
    Estes, B.
    Mahdessian, Diana
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Lundberg, Emma
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Wadsworth, P.
    Lamond, A. I.
    Proteomic analysis of cell cycle progression in asynchronous cultures, including mitotic subphases, using PRIMMUS2017In: eLIFE, E-ISSN 2050-084X, Vol. 6, article id e27574Article in journal (Refereed)
    Abstract [en]

    The temporal regulation of protein abundance and post-translational modifications is a key feature of cell division. Recently, we analysed gene expression and protein abundance changes during interphase under minimally perturbed conditions (Ly et al., 2014, 2015). Here, we show that by using specific intracellular immunolabelling protocols, FACS separation of interphase and mitotic cells, including mitotic subphases, can be combined with proteomic analysis by mass spectrometry. Using this PRIMMUS (PRoteomic analysis of Intracellular iMMUnolabelled cell Subsets) approach, we now compare protein abundance and phosphorylation changes in interphase and mitotic fractions from asynchronously growing human cells. We identify a set of 115 phosphorylation sites increased during G2, termed ‘early risers’. This set includes phosphorylation of S738 on TPX2, which we show is important for TPX2 function and mitotic progression. Further, we use PRIMMUS to provide the first a proteome-wide analysis of protein abundance remodeling between prophase, prometaphase and anaphase.

  • 5.
    Nakane, Takanori
    et al.
    MRC Lab Mol Biol, Cambridge, England..
    Kimanius, Dari
    Lindahl, Erik
    KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences (SCI), Physics.
    Scheres, Sjors H. W.
    MRC Lab Mol Biol, Cambridge, England..
    Characterisation of molecular motions in cryo-EM single-particle data by multi-body refinement in RELION2018In: eLIFE, E-ISSN 2050-084X, Vol. 7, article id e36861Article in journal (Refereed)
    Abstract [en]

    Macromolecular complexes that exhibit continuous forms of structural flexibility pose a challenge for many existing tools in cryo-EM single-particle analysis. We describe a new tool, called multi-body refinement, which models flexible complexes as a user-defined number of rigid bodies that move independently from each other. Using separate focused refinements with iteratively improved partial signal subtraction, the new tool generates improved reconstructions for each of the defined bodies in a fully automated manner. Moreover, using principal component analysis on the relative orientations of the bodies over all particle images in the data set, we generate movies that describe the most important motions in the data. Our results on two test cases, a cytoplasmic ribosome from Plasmodium falciparum, and the spliceosomal B-complex from yeast, illustrate how multi-body refinement can be useful to gain unique insights into the structure and dynamics of large and flexible macromolecular complexes.

  • 6. Pateraki, Irini
    et al.
    Andersen-Ranberg, Johan
    Jensen, Niels Bjerg
    Wubshet, Sileshi Gizachew
    Heskes, Allison Maree
    Forman, Victor
    Hallström, Björn M.
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Hamberger, Britta
    Motawia, Mohammed Saddik
    Olsen, Carl Erik
    Staerk, Dan
    Hansen, Jorgen
    Moller, Birger Lindberg
    Hamberger, Bjorn
    Total biosynthesis of the cyclic AMP booster for skolin from Coleus forskohlii2017In: eLIFE, E-ISSN 2050-084X, Vol. 6, article id e23001Article in journal (Refereed)
    Abstract [en]

    Forskolin is a unique structurally complex labdane-type diterpenoid used in the treatment of glaucoma and heart failure based on its activity as a cyclic AMP booster. Commercial production of forskolin relies exclusively on extraction from its only known natural source, the plant Coleus forskohlii, in which forskolin accumulates in the root cork. Here, we report the discovery of five cytochrome P450s and two acetyltransferases which catalyze a cascade of reactions converting the forskolin precursor 13R-manoyl oxide into forskolin and a diverse array of additional labdane-type diterpenoids. A minimal set of three P450s in combination with a single acetyl transferase was identified that catalyzes the conversion of 13R-manoyl oxide into forskolin as demonstrated by transient expression in Nicotiana benthamiana. The entire pathway for forskolin production from glucose encompassing expression of nine genes was stably integrated into Saccharomyces cerevisiae and afforded forskolin titers of 40 mg/L.

  • 7.
    Pernemalm, Maria
    et al.
    Karolinska Inst, Stockholm, Sweden.;Sci Life Lab, Proteogen, Solna, Sweden..
    Sandberg, AnnSofi
    Karolinska Inst, Stockholm, Sweden..
    Zhu, Yafeng
    Karolinska Inst, Stockholm, Sweden.;Sci Life Lab, Proteogen, Solna, Sweden..
    Boekel, Jorrit
    Karolinska Inst, Stockholm, Sweden.;Sci Life Lab, Proteogen, Solna, Sweden..
    Tamburro, Davide
    Karolinska Inst, Stockholm, Sweden..
    Schwenk, Jochen M.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
    Bjork, Albin
    Karolinska Inst, Stockholm, Sweden..
    Wahren-Herlenius, Marie
    Karolinska Inst, Stockholm, Sweden..
    Amark, Hanna
    Karolinska Inst, Stockholm, Sweden..
    Ostenson, Claes-Goran
    Karolinska Inst, Stockholm, Sweden..
    Westgren, Magnus
    Karolinska Inst, Stockholm, Sweden..
    Lehtio, Janne
    Karolinska Inst, Stockholm, Sweden.;Sci Life Lab, Proteogen, Solna, Sweden..
    In-depth human plasma proteome analysis captures tissue proteins and transfer of protein variants across the placenta2019In: eLIFE, E-ISSN 2050-084X, Vol. 8, article id e41608Article in journal (Refereed)
    Abstract [en]

    Here, we present a method for in-depth human plasma proteome analysis based on high-resolution isoelectric focusing HiRIEF LC-MS/MS, demonstrating high proteome coverage, reproducibility and the potential for liquid biopsy protein profiling. By integrating genomic sequence information to the MS-based plasma proteome analysis, we enable detection of single amino acid variants and for the first time demonstrate transfer of multiple protein variants between mother and fetus across the placenta. We further show that our method has the ability to detect both low abundance tissue-annotated proteins and phosphorylated proteins in plasma, as well as quantitate differences in plasma proteomes between the mother and the newborn as well as changes related to pregnancy.

  • 8. Regev, A
    et al.
    Lundberg, Emma
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Protein Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab. Danish Tech Univ, Denmark.
    Yosef, Nir
    et al.,
    The Human Cell Atlas2017In: eLIFE, E-ISSN 2050-084X, Vol. 6, article id e27041Article in journal (Refereed)
    Abstract [en]

    The recent advent of methods for high-throughput single-cell molecular profiling has catalyzed a growing sense in the scientific community that the time is ripe to complete the 150-year-old effort to identify all cell types in the human body. The Human Cell Atlas Project is an international collaborative effort that aims to define all human cell types in terms of distinctive molecular profiles (such as gene expression profiles) and to connect this information with classical cellular descriptions (such as location and morphology). An open comprehensive reference map of the molecular state of cells in healthy human tissues would propel the systematic study of physiological states, developmental trajectories, regulatory circuitry and interactions of cells, and also provide a framework for understanding cellular dysregulation in human disease. Here we describe the idea, its potential utility, early proofs-of-concept, and some design considerations for the Human Cell Atlas, including a commitment to open data, code, and community.

  • 9. Vijayvargia, Ravi
    et al.
    Epand, Raquel
    Leitner, Alexander
    Jung, Taeyang
    KTH, School of Technology and Health (STH), Basic Science and Biomedicine, Structural Biotechnology. Korea Adv Inst Sci & Technol, KAIST Inst BioCentury, Korea.
    Shin, Baehyun
    Jung, Roy
    Lloret, Alejandro
    Atwal, Randy Singh
    Lee, Hyeongseok
    Lee, Jong-Min
    Aebersold, Ruedi
    Hebert, Hans
    KTH, School of Technology and Health (STH), Basic Science and Biomedicine, Structural Biotechnology.
    Song, Ji-Joon
    Seong, Ihn Sik
    Huntingtin's spherical solenoid structure enables polyglutamine tract-dependent modulation of its structure and function2016In: eLIFE, E-ISSN 2050-084X, Vol. 5, article id e11184Article in journal (Refereed)
    Abstract [en]

    The polyglutamine expansion in huntingtin protein causes Huntington's disease. Here, we investigated structural and biochemical properties of huntingtin and the effect of the polyglutamine expansion using various biophysical experiments including circular dichroism, single particle electron microscopy and cross-linking mass spectrometry. Huntingtin is likely composed of five distinct domains and adopts a spherical alpha-helical solenoid where the amino-terminal and carboxyl-terminal regions fold to contain a circumscribed central cavity. Interestingly, we showed that the polyglutamine expansion increases alpha-helical properties of huntingtin and affects the intramolecular interactions among the domains. Our work delineates the structural characteristics of full-length huntingtin, which are affected by the polyglutamine expansion, and provides an elegant solution to the apparent conundrum of how the extreme amino-terminal polyglutamine tract confers a novel property on huntingtin, causing the disease.

  • 10.
    Zivanov, Jasenko
    et al.
    MRC, Lab Mol Biol, Cambridge, England..
    Nakane, Takanori
    MRC, Lab Mol Biol, Cambridge, England..
    Forsberg, Björn O.
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden..
    Kimanius, Dari
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden..
    Hagen, Wim J. H.
    European Mol Biol Lab, Struct & Computat Biol Unit, Heidelberg, Germany.;European Mol Biol Lab, Cryoelectron Microscopy Serv Platform, Heidelberg, Germany..
    Lindahl, Erik
    KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences (SCI), Applied Physics. Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden..
    Scheres, Sjors H. W.
    MRC, Lab Mol Biol, Cambridge, England..
    New tools for automated high-resolution cryo-EM structure determination in RELION-32018In: eLIFE, E-ISSN 2050-084X, Vol. 7, article id e42166Article in journal (Refereed)
    Abstract [en]

    Here, we describe the third major release of RELION. CPU-based vector acceleration has been added in addition to GPU support, which provides flexibility in use of resources and avoids memory limitations. Reference-free autopicking with Laplacian-of-Gaussian filtering and execution of jobs from python allows non-interactive processing during acquisition, including 2D-classification, de novo model generation and 3D-classification. Per-particle refinement of CTF parameters and correction of estimated beam tilt provides higher resolution reconstructions when particles are at different heights in the ice, and/or coma-free alignment has not been optimal. Ewald sphere curvature correction improves resolution for large particles. We illustrate these developments with publicly available data sets: together with a Bayesian approach to beam-induced motion correction it leads to resolution improvements of 0.2-0.7 angstrom compared to previous RELION versions.

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