Structural basis of plp2-mediated cytoskeletal protein folding by TRiC/CCT

Sci Adv. 2023 Mar 17;9(11):eade1207. doi: 10.1126/sciadv.ade1207. Epub 2023 Mar 15.

Abstract

The cytoskeletal proteins tubulin and actin are the obligate substrates of TCP-1 ring complex/Chaperonin containing TCP-1 (TRiC/CCT), and their folding involves co-chaperone. Through cryo-electron microscopy analysis, we present a more complete picture of TRiC-assisted tubulin/actin folding along TRiC adenosine triphosphatase cycle, under the coordination of co-chaperone plp2. In the open S1/S2 states, plp2 and tubulin/actin engaged within opposite TRiC chambers. Notably, we captured an unprecedented TRiC-plp2-tubulin complex in the closed S3 state, engaged with a folded full-length β-tubulin and loaded with a guanosine triphosphate, and a plp2 occupying opposite rings. Another closed S4 state revealed an actin in the intermediate folding state and a plp2. Accompanying TRiC ring closure, plp2 translocation could coordinate substrate translocation on the CCT6 hemisphere, facilitating substrate stabilization and folding. Our findings reveal the folding mechanism of the major cytoskeletal proteins tubulin/actin under the coordination of the biogenesis machinery TRiC and plp2 and extend our understanding of the links between cytoskeletal proteostasis and related human diseases.

MeSH terms

  • Actins* / metabolism
  • Cryoelectron Microscopy
  • Cytoskeletal Proteins* / metabolism
  • Humans
  • MARVEL Domain-Containing Proteins* / metabolism
  • Molecular Chaperones / metabolism
  • Protein Folding
  • Proteolipids
  • Tubulin* / metabolism

Substances

  • Actins
  • MARVEL Domain-Containing Proteins
  • Molecular Chaperones
  • PLP2 protein, human
  • Proteolipids
  • Tubulin
  • Cytoskeletal Proteins