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  • 1.
    Asquith, Nathan L.
    et al.
    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..
    Duval, Cedric
    Univ Leeds, Leeds Inst Cardiovasc & Metab Med, Sch Med, Discovery & Translat Sci Dept, Leeds, England..
    Zhmurov, Artem
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Electrical Engineering and Computer Science (EECS), Centres, Centre for High Performance Computing, PDC. EuroCC Natl Competence Ctr Sweden, Stockholm, Sweden.
    Baker, Stephen R.
    Univ Leeds, Leeds Inst Cardiovasc & Metab Med, Sch Med, Discovery & Translat Sci Dept, Leeds, England..
    McPherson, Helen R.
    Univ Leeds, Leeds Inst Cardiovasc & Metab Med, Sch Med, Discovery & Translat Sci Dept, Leeds, England..
    Domingues, Marco M.
    Univ Leeds, Leeds Inst Cardiovasc & Metab Med, Sch Med, Discovery & Translat Sci Dept, Leeds, England.;Univ Lisbon, Inst Mol Med, Fac Med, Lisbon, Portugal..
    Connell, Simon D. A.
    Univ Leeds, Sch Phys & Astron, Mol & Nanoscale Phys Grp, Leeds, England..
    Barsegov, Valeri
    Univ Massachusetts, Dept Chem, Lowell, MA USA..
    Ariens, Robert A. S.
    Univ Leeds, Leeds Inst Cardiovasc & Metab Med, Sch Med, Discovery & Translat Sci Dept, Leeds, England.;Univ Leeds, Leeds Inst Cardiovasc & Metab Med, Discovery & Translat Sci Dept, Leeds LS2 9JT, England..
    Fibrin protofibril packing and clot stability are enhanced by extended knob-hole interactions and catch-slip bonds2022In: Blood Advances, ISSN 2473-9529, Vol. 6, no 13, p. 4015-4027Article in journal (Refereed)
    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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