7XC5

Crystal structure of the ANK domain of CLPB

Summary for 7XC5

• Entry DOI: 10.2210/pdb7xc5/pdb
• Descriptor: Isoform 2 of Caseinolytic peptidase B protein homolog (2 entities in total)
• Functional Keywords: ank repeat, transport protein, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 22189.71

Authors

Liu, Y.,Wu, D.,Lu, G.,Gao, N.,Lin, J. (deposition date: 2022-03-23, release date: 2023-01-18, Last modification date: 2024-05-29)

Primary citation

Wu, D.,Liu, Y.,Dai, Y.,Wang, G.,Lu, G.,Chen, Y.,Li, N.,Lin, J.,Gao, N.
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.
Plos Biol., 21:e3001987-e3001987, 2023

PubMed Abstract: 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.

PubMed: 36745679
DOI: 10.1371/journal.pbio.3001987

Experimental method

X-RAY DIFFRACTION (2.1 Å)