Structural Investigation of the Interaction Between High Molecular Weight Kininogen and gC1qR.

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Ma, Yewei (2025) Structural Investigation of the Interaction Between High Molecular Weight Kininogen and gC1qR. PhD thesis, University of Nottingham.

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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: Thesis (University of Nottingham only) (PhD)
Supervisors: Emsley, Jonas
Dreveny, Ingrid
Keywords: haemostasis, thrombosis, protein binding, High-molecular-weight kininogen, gC1qR
Subjects: Q Science > QP Physiology > QP501 Animal biochemistry
R Medicine > RC Internal medicine
Faculties/Schools: UK Campuses > Faculty of Science > School of Pharmacy
Item ID: 82297
Depositing User: Ma, Yewei
Date Deposited: 30 Oct 2025 14:18
Last Modified: 30 Oct 2025 14:18
URI: https://eprints.nottingham.ac.uk/id/eprint/82297

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