7ttr Citations

Unique structural features govern the activity of a human mitochondrial AAA+ disaggregase, Skd3.

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.

Articles - 7ttr mentioned but not cited (1)

  1. Unique structural features govern the activity of a human mitochondrial AAA+ disaggregase, Skd3. Cupo RR, Rizo AN, Braun GA, Tse E, Chuang E, Gupta K, Southworth DR, Shorter J. Cell Rep 40 111408 (2022)


Articles citing this publication (6)

  1. 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. Wu D, Liu Y, Dai Y, Wang G, Lu G, Chen Y, Li N, Lin J, Gao N. PLoS Biol 21 e3001987 (2023)
  2. Deciphering the mechanism and function of Hsp100 unfoldases from protein structure. Lee G, Kim RS, Lee SB, Lee S, Tsai FTF. Biochem Soc Trans 50 1725-1736 (2022)
  3. Dodecamer assembly of a metazoan AAA+ chaperone couples substrate extraction to refolding. Gupta A, Lentzsch AM, Siegel A, Yu Z, Chio US, Cheng Y, Shan SO. Sci Adv 9 eadf5336 (2023)
  4. Structural basis of impaired disaggregase function in the oxidation-sensitive SKD3 mutant causing 3-methylglutaconic aciduria. Lee S, Lee SB, Sung N, Xu WW, Chang C, Kim HE, Catic A, Tsai FTF. Nat Commun 14 2028 (2023)
  5. CLPB disaggregase dysfunction impacts the functional integrity of the proteolytic SPY complex. Baker MJ, Blau KU, Anderson AJ, Palmer CS, Fielden LF, Crameri JJ, Milenkovic D, Thorburn DR, Frazier AE, Langer T, Stojanovski D. J Cell Biol 223 e202305087 (2024)
  6. The Listeria monocytogenes persistence factor ClpL is a potent stand-alone disaggregase. Bohl V, Hollmann NM, Melzer T, Katikaridis P, Meins L, Simon B, Flemming D, Sinning I, Hennig J, Mogk A. Elife 12 RP92746 (2024)