7TTS

Skd3, hexamer, filtered

Summary for 7TTS

• Entry DOI: 10.2210/pdb7tts/pdb
• EMDB information: 26121 26122
• Descriptor: Caseinolytic peptidase B protein homolog, Beta-casein, ADENOSINE-5'-DIPHOSPHATE, ... (5 entities in total)
• Functional Keywords: aaa+, cryoem, chaperone
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 7
• Total formula weight: 424067.34

Authors

Rizo, A.N.,Cupo, R.R. (deposition date: 2022-02-01, release date: 2022-09-28, Last modification date: 2024-06-12)

Primary citation

Cupo, R.R.,Rizo, A.N.,Braun, G.A.,Tse, E.,Chuang, E.,Gupta, K.,Southworth, D.R.,Shorter, J.
Unique structural features govern the activity of a human mitochondrial AAA+ disaggregase, Skd3.
Cell Rep, 40:111408-111408, 2022

PubMed Abstract: The AAA+ protein, Skd3 (human CLPB), solubilizes proteins in the mitochondrial intermembrane space, which is critical for human health. Skd3 variants with defective protein-disaggregase activity cause severe congenital neutropenia (SCN) and 3-methylglutaconic aciduria type 7 (MGCA7). How Skd3 disaggregates proteins remains poorly understood. Here, we report a high-resolution structure of a Skd3-substrate complex. Skd3 adopts a spiral hexameric arrangement that engages substrate via pore-loop interactions in the nucleotide-binding domain (NBD). Substrate-bound Skd3 hexamers stack head-to-head via unique, adaptable ankyrin-repeat domain (ANK)-mediated interactions to form dodecamers. Deleting the ANK linker region reduces dodecamerization and disaggregase activity. We elucidate apomorphic features of the Skd3 NBD and C-terminal domain that regulate disaggregase activity. We also define how Skd3 subunits collaborate to disaggregate proteins. Importantly, SCN-linked subunits sharply inhibit disaggregase activity, whereas MGCA7-linked subunits do not. These advances illuminate Skd3 structure and mechanism, explain SCN and MGCA7 inheritance patterns, and suggest therapeutic strategies.

PubMed: 36170828
DOI: 10.1016/j.celrep.2022.111408

Experimental method

ELECTRON MICROSCOPY (2.9 Å)