The structural basis of substrate recognition by the eukaryotic chaperonin TRiC/CCT

Lukasz A. Joachimiak, Thomas Walzthoeni, Corey W. Liu, Ruedi Aebersold, Judith Frydman

Research output: Contribution to journalArticle

69 Citations (Scopus)

Abstract

The eukaryotic chaperonin TRiC (also called CCT) is the obligate chaperone for many essential proteins. TRiC is hetero-oligomeric, comprising two stacked rings of eight different subunits each. Subunit diversification from simpler archaeal chaperonins appears linked to proteome expansion. Here, we integrate structural, biophysical, and modeling approaches to identify the hitherto unknown substrate-binding site in TRiC and uncover the basis of substrate recognition. NMR and modeling provided a structural model of a chaperonin-substrate complex. Mutagenesis and crosslinking-mass spectrometry validated the identified substrate-binding interface and demonstrate that TRiC contacts full-length substrates combinatorially in a subunit-specific manner. The binding site of each subunit has a distinct, evolutionarily conserved pattern of polar and hydrophobic residues specifying recognition of discrete substrate motifs. The combinatorial recognition of polypeptides broadens the specificity of TRiC and may direct the topology of bound polypeptides along a productive folding trajectory, contributing to TRiC's unique ability to fold obligate substrates.

Original languageEnglish (US)
Pages (from-to)1042-1055
Number of pages14
JournalCell
Volume159
Issue number5
DOIs
StatePublished - Nov 20 2014
Externally publishedYes

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Chaperonin Containing TCP-1
Chaperonins
Substrates
Binding Sites
Peptides
Structural Models
Proteome
Mutagenesis
Mass Spectrometry
Proteins
Crosslinking
Mass spectrometry
Trajectories
Nuclear magnetic resonance
Topology

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

The structural basis of substrate recognition by the eukaryotic chaperonin TRiC/CCT. / Joachimiak, Lukasz A.; Walzthoeni, Thomas; Liu, Corey W.; Aebersold, Ruedi; Frydman, Judith.

In: Cell, Vol. 159, No. 5, 20.11.2014, p. 1042-1055.

Research output: Contribution to journalArticle

Joachimiak, LA, Walzthoeni, T, Liu, CW, Aebersold, R & Frydman, J 2014, 'The structural basis of substrate recognition by the eukaryotic chaperonin TRiC/CCT', Cell, vol. 159, no. 5, pp. 1042-1055. https://doi.org/10.1016/j.cell.2014.10.042
Joachimiak, Lukasz A. ; Walzthoeni, Thomas ; Liu, Corey W. ; Aebersold, Ruedi ; Frydman, Judith. / The structural basis of substrate recognition by the eukaryotic chaperonin TRiC/CCT. In: Cell. 2014 ; Vol. 159, No. 5. pp. 1042-1055.
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