National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
米国
引用
ジャーナル: Nat Commun / 年: 2022 タイトル: Structures reveal a key mechanism of WAVE regulatory complex activation by Rac1 GTPase. 著者: Bojian Ding / Sheng Yang / Matthias Schaks / Yijun Liu / Abbigale J Brown / Klemens Rottner / Saikat Chowdhury / Baoyu Chen / 要旨: The Rho-family GTPase Rac1 activates the WAVE regulatory complex (WRC) to drive Arp2/3 complex-mediated actin polymerization in many essential processes. Rac1 binds to WRC at two distinct sites-the ...The Rho-family GTPase Rac1 activates the WAVE regulatory complex (WRC) to drive Arp2/3 complex-mediated actin polymerization in many essential processes. Rac1 binds to WRC at two distinct sites-the A and D sites. Precisely how Rac1 binds and how the binding triggers WRC activation remain unknown. Here we report WRC structures by itself, and when bound to single or double Rac1 molecules, at ~3 Å resolutions by cryogenic-electron microscopy. The structures reveal that Rac1 binds to the two sites by distinct mechanisms, and binding to the A site, but not the D site, drives WRC activation. Activation involves a series of unique conformational changes leading to the release of sequestered WCA (WH2-central-acidic) polypeptide, which stimulates the Arp2/3 complex to polymerize actin. Together with biochemical and cellular analyses, the structures provide a novel mechanistic understanding of how the Rac1-WRC-Arp2/3-actin signaling axis is regulated in diverse biological processes and diseases.
超分子 #1: WAVE regulatory complex with Rac1 bound to A and D sites
超分子
名称: WAVE regulatory complex with Rac1 bound to A and D sites タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: #1-#7
由来(天然)
生物種: Homo sapiens (ヒト)
分子量
理論値: 380 KDa
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分子 #1: Cytoplasmic FMR1-interacting protein 1
分子
名称: Cytoplasmic FMR1-interacting protein 1 / タイプ: protein_or_peptide / ID: 1 詳細: This construct contains two additional uncleaved residues "GA" in the N terminus from the construct design and purification procedure. Densities for these residues are not observed in the map ...詳細: This construct contains two additional uncleaved residues "GA" in the N terminus from the construct design and purification procedure. Densities for these residues are not observed in the map and were not included in the sample sequence to avoid numbering shifts. コピー数: 1 / 光学異性体: LEVO
名称: Nck-associated protein 1 / タイプ: protein_or_peptide / ID: 2 詳細: This construct contains two additional uncleaved residues "GA" in the N terminus from the construct design and purification procedure. Densities for these residues are not observed in the map ...詳細: This construct contains two additional uncleaved residues "GA" in the N terminus from the construct design and purification procedure. Densities for these residues are not observed in the map and were not included in the sample sequence to avoid numbering shifts. コピー数: 1 / 光学異性体: LEVO
分子 #3: Wiskott-Aldrich syndrome protein family member 1
分子
名称: Wiskott-Aldrich syndrome protein family member 1 / タイプ: protein_or_peptide / ID: 3 詳細: Residues 231-248 are inserted as a flexible linker sequence. This construct contains two additional uncleaved residues "GA" in the N terminus from the construct design and purification ...詳細: Residues 231-248 are inserted as a flexible linker sequence. This construct contains two additional uncleaved residues "GA" in the N terminus from the construct design and purification procedure. Densities for these residues are not observed in the map and were not included in the sample sequence to avoid numbering shifts. コピー数: 1 / 光学異性体: LEVO
UniProtKB: Actin-binding protein WASF1, Actin-binding protein WASF1
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分子 #4: Protein BRICK1
分子
名称: Protein BRICK1 / タイプ: protein_or_peptide / ID: 4 詳細: This construct contains uncleaved residues "GHMGAA" in the N terminus from the construct design and purification procedure. Densities for the residues are not observed in the map and were not ...詳細: This construct contains uncleaved residues "GHMGAA" in the N terminus from the construct design and purification procedure. Densities for the residues are not observed in the map and were not included in the sample sequence to avoid numbering shifts. コピー数: 1 / 光学異性体: LEVO
名称: Abl interactor 2 / タイプ: protein_or_peptide / ID: 5 詳細: The sequence only contains residues 1-158. Also, there are two additional uncleaved residues "GH" in the N terminus from the construct design and purification procedure. Densities for these ...詳細: The sequence only contains residues 1-158. Also, there are two additional uncleaved residues "GH" in the N terminus from the construct design and purification procedure. Densities for these residues are not observed in the map and were not included in the sample sequence to avoid numbering shifts. コピー数: 1 / 光学異性体: LEVO