7WPP

Cryo-EM structure of VWF D'D3 dimer complexed with D1D2 at 2.85 angstron resolution (1 unit)

Summary for 7WPP

• Entry DOI: 10.2210/pdb7wpp/pdb
• Related: 7WN4 7WN6 7WPQ 7WQT
• EMDB information: 32621 32622 32687 32688 32691 32692 32713
• Descriptor: von Willebrand antigen 2, von Willebrand factor, CALCIUM ION, ... (4 entities in total)
• Functional Keywords: blood, vwf, von willebrand factor, von willebrand disease, blood coagulation, blood clotting, multimer assembly, vwf assembly, d'd3 domain, d1d2 domain, d'd3 dimer, d1d2 dimer, vwf tube, repeating unit
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 273773.57

Authors

Zeng, J.W.,Shu, Z.M.,Zhou, A.W. (deposition date: 2022-01-24, release date: 2022-05-25, Last modification date: 2022-06-15)

Primary citation

Zeng, J.,Shu, Z.,Liang, Q.,Zhang, J.,Wu, W.,Wang, X.,Zhou, A.
Structural basis of von Willebrand factor multimerization and tubular storage.
Blood, 139:3314-3324, 2022

PubMed Abstract: The von Willebrand factor (VWF) propeptide (domains D1D2) is essential for the assembly of VWF multimers and its tubular storage in Weibel-Palade bodies. However, detailed molecular mechanism underlying this propeptide dependence is unclear. Here, we prepared Weibel-Palade body-like tubules using the N-terminal fragment of VWF and solved the cryo-electron microscopy structures of the tubule at atomic resolution. Detailed structural and biochemical analysis indicate that the propeptide forms a homodimer at acidic pH through the D2:D2 binding interface and then recruits 2 D'D3 domains, forming an intertwined D1D2D'D3 homodimer in essence. Stacking of these homodimers by the intermolecular D1:D2 interfaces brings 2 D3 domains face-to-face and facilitates their disulfide linkages and multimerization of VWF. Sequential stacking of these homodimers leads to a right-hand helical tubule for VWF storage. The clinically identified VWF mutations in the propeptide disrupted different steps of the assembling process, leading to diminished VWF multimers in von Willebrand diseases (VWD). Overall, these results indicate that the propeptide serves as a pH-sensing template for VWF multimerization and tubular storage. This sheds light on delivering normal propeptide as a template to rectify the defects in multimerization of VWD mutants.

PubMed: 35148377
DOI: 10.1182/blood.2021014729

Experimental method

ELECTRON MICROSCOPY (2.85 Å)