8OS5

Crystal structure of the Factor XII heavy chain reveals an interlocking dimer with a FnII to kringle domain interaction

Summary for 8OS5

• Entry DOI: 10.2210/pdb8os5/pdb
• Descriptor: Coagulation factor XII-Mie (1 entity in total)
• Functional Keywords: factor xii heavy chain crystal structure thrombosis kringle domain, blood clotting
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 3
• Total formula weight: 100503.13

Authors

Li, C.,Saleem, M.,Kaira, B.G.,Brown, A.,Wilson, C.,Philippou, H.,Emsley, J. (deposition date: 2023-04-18, release date: 2024-03-27, Last modification date: 2024-10-23)

Primary citation

Kaira, B.G.,Slater, A.,McCrae, K.R.,Dreveny, I.,Sumya, U.,Mutch, N.J.,Searle, M.,Emsley, J.
Factor XII and kininogen asymmetric assembly with gC1qR/C1QBP/P32 is governed by allostery.
Blood, 136:1685-1697, 2020

PubMed Abstract: The contact system is composed of factor XII (FXII), prekallikrein (PK), and cofactor high-molecular-weight kininogen (HK). The globular C1q receptor (gC1qR) has been shown to interact with FXII and HK. We reveal the FXII fibronectin type II domain (FnII) binds gC1qR in a Zn2+-dependent fashion and determined the complex crystal structure. FXIIFnII binds the gC1qR trimer in an asymmetric fashion, with residues Arg36 and Arg65 forming contacts with 2 distinct negatively charged pockets. gC1qR residues Asp185 and His187 coordinate a Zn2+ adjacent to the FXII-binding site, and a comparison with the ligand-free gC1qR crystal structure reveals the anionic G1-loop becomes ordered upon FXIIFnII binding. Additional conformational changes in the region of the Zn2+-binding site reveal an allosteric basis for Zn2+ modulation of FXII binding. Mutagenesis coupled with surface plasmon resonance demonstrate the gC1qR Zn2+ site contributes to FXII binding, and plasma-based assays reveal gC1qR stimulates coagulation in a FXII-dependent manner. Analysis of the binding of HK domain 5 (HKD5) to gC1qR shows only 1 high-affinity binding site per trimer. Mutagenesis studies identify a critical G3-loop located at the center of the gC1qR trimer, suggesting steric occlusion as the mechanism for HKD5 asymmetric binding. Gel filtration experiments reveal that gC1qR clusters FXII and HK into a higher-order 500-kDa ternary complex. These results support the conclusion that extracellular gC1qR can act as a chaperone to cluster contact factors, which may be a prelude for initiating the cascades that drive bradykinin generation and the intrinsic pathway of coagulation.

PubMed: 32559765
DOI: 10.1182/blood.2020004818

Experimental method

X-RAY DIFFRACTION (3.4 Å)