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-Structure paper
タイトル | Structural basis of von Willebrand factor multimerization and tubular storage. |
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ジャーナル・号・ページ | Blood, Vol. 139, Issue 22, Page 3314-3324, Year 2022 |
掲載日 | 2022年6月2日 |
著者 | Jianwei Zeng / Zimei Shu / Qian Liang / Jing Zhang / Wenman Wu / Xuefeng Wang / Aiwu Zhou / |
PubMed 要旨 | 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 ...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. |
リンク | Blood / PubMed:35148377 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 2.85 - 11.4 Å |
構造データ | EMDB-32687, PDB-7wpp: EMDB-32688, PDB-7wpq: EMDB-32689, PDB-7wpr: EMDB-32690, PDB-7wps: EMDB-32691: EMDB-32692: EMDB-32713, PDB-7wqt: |
化合物 | ChemComp-CA: ChemComp-NAG: |
由来 |
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キーワード | BLOOD CLOTTING / blood / VWF / von Willebrand factor / von Willebrand disease / blood coagulation / multimer assembly / VWF assembly / D'D3 domain / D1D2 domain / D'D3 dimer / D1D2 Dimer / VWF Tube / repeating unit |