Structural Investigation of the Interaction Between High Molecular Weight Kininogen and gC1qR.
Publication Date
October 15, 2025
Creator
Abstract
The intrinsic (contact) pathway is essential for initiating blood coagulation, mediating inflammatory responses, and contributing to thrombosis. Activation begins when factor XII (FXII) and High Molecular Weight Kininogen (HMWK) bind prekallikrein (PK) at gC1qR on the cell surface. HMWK serves as a cofactor, presenting factor XI and PK to FXII which is already bound to gC1qR. Both FXII and HMWK can interact with gC1qR in a zinc-dependent way, initiating a proteolytic cascade that release bradykinin which leads to inflammation and fibrin clot formation. Domain 5 of HMWK mediates its binding to gC1qR.
Structural analyses reveal three distinct binding modes between gC1qR and HMWK, with cryo-EM demonstrating HMWK's ability to bridge two gC1qR molecules through flexible interactions. X-ray crystallography further identifies a Zn²⁺-dependent conformational change in gC1qR's loop 3 that enables specific engagement with HMWK domain 5. Factor XII binding induces structural rearrangements in this complex, suggesting a dynamic regulatory mechanism for contact activation at cell surfaces. The statement highlights key findings about the interaction between gC1qR and HMWK, as well as the roles of Zn²⁺ and FXII in modulating this interaction during contact activation at the cell surface.
Item Type
ethesis
Thesis Type
PhD
Supervisors
Subjects (LC)
Associated Schools / Departments
School of Pharmacy (UK)
eprints ID
82297
UoN Repository URI
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Name
Yewei PhD Thesis 11.pdf
Type
Full-text
Description
Examined
Size
7.77 MB
Format
Adobe PDF
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