7WPQ

Cryo-EM structure of VWF D'D3 dimer complexed with D1D2 at 3.27 angstron resolution (2 units)

7WPQ の概要

• エントリーDOI: 10.2210/pdb7wpq/pdb
• 関連するPDBエントリー: 7WN4 7WN6 7WPP 7WQT
• EMDBエントリー: 32621 32622 32687 32688 32691 32692 32713
• 分子名称: von Willebrand antigen 2, von Willebrand factor, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (4 entities in total)
• 機能のキーワード: 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
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 547707.46

構造登録者

Zeng, J.W.,Shu, Z.M.,Zhou, A.W. (登録日: 2022-01-24, 公開日: 2022-05-25, 最終更新日: 2024-10-09)

主引用文献

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

実験手法

ELECTRON MICROSCOPY (3.267 Å)