Structural Basis of Interfacial Flexibility in Fibrin Oligomers.
Fibrin is a filamentous network made in blood to stem bleeding; it forms when fibrinogen is converted into fibrin monomers that self-associate into oligomers and then to polymers. To gather structural insights into fibrin formation and properties, we combined high-resolution atomic force microscopy of fibrin(ogen) oligomers and molecular modeling of crystal structures of fibrin(ogen) and its fragments. We provided a structural basis for the intermolecular flexibility of single-stranded fibrin(ogen) oligomers and identified a hinge region at the D:D inter-monomer junction. Following computational reconstruction of the missing portions, we recreated the full-atomic structure of double-stranded fibrin oligomers that was validated by quantitative comparison with the experimental images. We characterized previously unknown intermolecular binding contacts at the D:D and D:E:D interfaces, which drive oligomerization and reinforce the intra- and inter-strand connections in fibrin besides the known knob-hole bonds. The atomic models provide valuable insights into the submolecular mechanisms of fibrin polymerization.
Moscow Institute of Physics & Technology, Dolgoprudny, Moscow Region 141700, Russian Federation.
Artem
A
Zhmurov
Department of Cell & Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Anna D
AD
Protopopova
Department of Cell & Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan 420012, Russian Federation.
Rustem I
RI
Litvinov
Moscow Institute of Physics & Technology, Dolgoprudny, Moscow Region 141700, Russian Federation.
Pavel
P
Zhukov
Department of Cell & Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Alexander R
AR
Mukhitov
Department of Cell & Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: weisel@mail.med.upenn.edu.
John W
JW
Weisel
Moscow Institute of Physics & Technology, Dolgoprudny, Moscow Region 141700, Russian Federation; Department of Chemistry, University of Massachusetts, Lowell, MA 01854, USA. Electronic address: valeri_barsegov@uml.edu.
Valeri
V
Barsegov
D001665:Binding Sites; D018360:Crystallography, X-Ray; D005337:Fibrin / Q000737:chemistry*; D005340:Fibrinogen / Q000737:chemistry*; D006801:Humans; D018625:Microscopy, Atomic Force; D008958:Models, Molecular; D058105:Polymerization; D011487:Protein Conformation
D005337:Fibrin; D005340:Fibrinogen
D:D interface; D:E:D interface; MD simulations on a GPU; fibrin; fibrin oligomers; fibrin polymerization; fibrinogen
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