Structure of the human TRiC/CCT Subunit 5 associated with hereditary sensory neuropathy

Sci Rep. 2017 Jun 16;7(1):3673. doi: 10.1038/s41598-017-03825-3.

Abstract

The human chaperonin TRiC consists of eight non-identical subunits, and its protein-folding activity is critical for cellular health. Misfolded proteins are associated with many human diseases, such as amyloid diseases, cancer, and neuropathies, making TRiC a potential therapeutic target. A detailed structural understanding of its ATP-dependent folding mechanism and substrate recognition is therefore of great importance. Of particular health-related interest is the mutation Histidine 147 to Arginine (H147R) in human TRiC subunit 5 (CCT5), which has been associated with hereditary sensory neuropathy. In this paper, we describe the crystal structures of CCT5 and the CCT5-H147R mutant, which provide important structural information for this vital protein-folding machine in humans. This first X-ray crystallographic study of a single human CCT subunit in the context of a hexadecameric complex can be expanded in the future to the other 7 subunits that form the TRiC complex.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenosine Diphosphate / chemistry
  • Adenosine Diphosphate / metabolism
  • Amino Acid Sequence
  • Chaperonin Containing TCP-1 / chemistry*
  • Chaperonin Containing TCP-1 / genetics*
  • Disease Susceptibility*
  • Hereditary Sensory and Autonomic Neuropathies / genetics*
  • Humans
  • Models, Molecular
  • Mutation
  • Protein Conformation
  • Protein Multimerization
  • Protein Subunits / chemistry
  • Protein Subunits / genetics
  • Structure-Activity Relationship

Substances

  • CCT5 protein, human
  • Protein Subunits
  • Adenosine Diphosphate
  • Chaperonin Containing TCP-1