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Fibrin protofibril packing and clot stability are enhanced by extended knob-hole interactions and catch-slip bonds
Univ Leeds, Leeds Inst Cardiovasc & Metab Med, Sch Med, Discovery & Translat Sci Dept, Leeds, England.;Boston Childrens Hosp, Harvard Med Sch, Vasc Biol Program, Karp Res Labs, Boston, MA USA..ORCID-id: 0000-0002-7073-825X
Univ Leeds, Leeds Inst Cardiovasc & Metab Med, Sch Med, Discovery & Translat Sci Dept, Leeds, England..ORCID-id: 0000-0002-4870-6542
KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för elektroteknik och datavetenskap (EECS), Centra, Parallelldatorcentrum, PDC. EuroCC Natl Competence Ctr Sweden, Stockholm, Sweden.
Univ Leeds, Leeds Inst Cardiovasc & Metab Med, Sch Med, Discovery & Translat Sci Dept, Leeds, England..ORCID-id: 0000-0002-3147-4925
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2022 (Engelska)Ingår i: Blood Advances, ISSN 2473-9529, Vol. 6, nr 13, s. 4015-4027Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Fibrin polymerization involves thrombin-mediated exposure of knobs on one monomer that bind to holes available on another, leading to the formation of fibers. In silico evidence has suggested that the classical A:a knob-hole interaction is enhanced by surrounding residues not directly involved in the binding pocket of hole a, via noncovalent interactions with knob A. We assessed the importance of extended knob-hole interactions by performing biochemical, biophysical, and in silico modeling studies on recombinant human fibrinogen variants with mutations at residues responsible for the extended interactions. Three single fibrinogen variants, yD297N, yE323Q, and yK356Q, and a triple variant yDEK (yD297N/yE323Q/yK356Q) were produced in a CHO (Chinese Hamster Ovary) cell expression system. Longitudinal protofibril growth probed by atomic force microscopy was disrupted for yD297N and enhanced for the yK356Q mutation. Initial polymerization rates were reduced for all variants in turbidimetric studies. Laser scanning confocal microscopy showed that yDEK and yE323Q produced denser clots, whereas yD297N and yK356Q were similar to wild type. Scanning electron microscopy and light scattering studies showed that fiber thickness and protofibril packing of the fibers were reduced for all variants. Clot viscoelastic analysis showed that only yDEK was more readily deformable. In silico modeling suggested that most variants displayed only slip-bond dissociation kinetics compared with biphasic catch-slip kinetics characteristics of wild type. These data provide new evidence for the role of extended interactions in supporting the classical knob-hole bonds involving catch-slip behavior in fibrin formation, clot structure, and clot mechanics.

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American Society of Hematology , 2022. Vol. 6, nr 13, s. 4015-4027
Nationell ämneskategori
Hematologi
Identifikatorer
URN: urn:nbn:se:kth:diva-316333DOI: 10.1182/bloodadvances.2022006977ISI: 000830364600009PubMedID: 35561308Scopus ID: 2-s2.0-85134329281OAI: oai:DiVA.org:kth-316333DiVA, id: diva2:1687030
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QC 20220812

Tillgänglig från: 2022-08-12 Skapad: 2022-08-12 Senast uppdaterad: 2022-08-12Bibliografiskt granskad

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Zhmurov, Artem

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Asquith, Nathan L.Duval, CedricZhmurov, ArtemBaker, Stephen R.Domingues, Marco M.
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Science for Life Laboratory, SciLifeLabParallelldatorcentrum, PDC
Hematologi

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