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-Structure paper
タイトル | Comprehensive structural characterization of the human AAA+ disaggregase CLPB in the apo- and substrate-bound states reveals a unique mode of action driven by oligomerization. |
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ジャーナル・号・ページ | PLoS Biol, Vol. 21, Issue 2, Page e3001987, Year 2023 |
掲載日 | 2023年2月6日 |
著者 | Damu Wu / Yan Liu / Yuhao Dai / Guopeng Wang / Guoliang Lu / Yan Chen / Ningning Li / Jinzhong Lin / Ning Gao / |
PubMed 要旨 | The human AAA+ ATPase CLPB (SKD3) is a protein disaggregase in the mitochondrial intermembrane space (IMS) and functions to promote the solubilization of various mitochondrial proteins. Loss-of- ...The human AAA+ ATPase CLPB (SKD3) is a protein disaggregase in the mitochondrial intermembrane space (IMS) and functions to promote the solubilization of various mitochondrial proteins. Loss-of-function CLPB mutations are associated with a few human diseases with neutropenia and neurological disorders. Unlike canonical AAA+ proteins, CLPB contains a unique ankyrin repeat domain (ANK) at its N-terminus. How CLPB functions as a disaggregase and the role of its ANK domain are currently unclear. Herein, we report a comprehensive structural characterization of human CLPB in both the apo- and substrate-bound states. CLPB assembles into homo-tetradecamers in apo-state and is remodeled into homo-dodecamers upon substrate binding. Conserved pore-loops (PLs) on the ATPase domains form a spiral staircase to grip and translocate the substrate in a step-size of 2 amino acid residues. The ANK domain is not only responsible for maintaining the higher-order assembly but also essential for the disaggregase activity. Interactome analysis suggests that the ANK domain may directly interact with a variety of mitochondrial substrates. These results reveal unique properties of CLPB as a general disaggregase in mitochondria and highlight its potential as a target for the treatment of various mitochondria-related diseases. |
リンク | PLoS Biol / PubMed:36745679 / PubMed Central |
手法 | EM (単粒子) / X線回折 |
解像度 | 2.1 - 7.5 Å |
構造データ | EMDB-33104, PDB-7xbk: EMDB-33105: Structure and mechanism of a mitochondrial AAA+ disaggregase CLPB EMDB-33106: Structure and mechanism of a mitochondrial AAA+ disaggregase CLPB EMDB-33109: Structure and mechanism of a mitochondrial AAA+ disaggregase CLPB EMDB-33110: Cry-EM structure of CLPB NBD organized in heptamer PDB-7xc5: |
化合物 | ChemComp-ATP: ChemComp-MG: ChemComp-HOH: |
由来 |
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キーワード | CHAPERONE / CLPB / AAA-ATPase / HYDROLASE / ANK repeat / TRANSPORT PROTEIN |