kth.sePublications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
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, 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.
Univ Leeds, Leeds Inst Cardiovasc & Metab Med, Sch Med, Discovery & Translat Sci Dept, Leeds, England..ORCID iD: 0000-0002-3147-4925
Show others and affiliations
2022 (English)In: Blood Advances, ISSN 2473-9529, Vol. 6, no 13, p. 4015-4027Article in journal (Refereed) 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.

Place, publisher, year, edition, pages
American Society of Hematology , 2022. Vol. 6, no 13, p. 4015-4027
National Category
Hematology
Identifiers
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
Note

QC 20220812

Available from: 2022-08-12 Created: 2022-08-12 Last updated: 2022-08-12Bibliographically approved

Open Access in DiVA

No full text in DiVA

Other links

Publisher's full textPubMedScopus

Authority records

Zhmurov, Artem

Search in DiVA

By author/editor
Asquith, Nathan L.Duval, CedricZhmurov, ArtemBaker, Stephen R.Domingues, Marco M.
By organisation
Science for Life Laboratory, SciLifeLabCentre for High Performance Computing, PDC
Hematology

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 47 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf