Identification of a consensus motif in substrates bound by a Type I Hsp40

Pradeep Kota, Daniel W. Summers, Hong Yu Ren, Douglas M. Cyr, Nikolay V. Dokholyan

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Protein aggregation is a hallmark of a large and diverse number of conformational diseases. Molecular chaperones of the Hsp40 family (Escherichia coli DnaJ homologs) recognize misfolded disease proteins and suppress the accumulation of toxic protein species. Type I Hsp40s are very potent at suppressing protein aggregation and facilitating the refolding of damaged proteins. Yet, the molecular mechanism for the recognition of nonnative polypeptides by Type I Hsp40s such as yeast Ydj1 is not clear. Here we computationally identify a unique motif that is selectively recognized by Ydj1p. The motif is characterized by the consensus sequence GX[LMQ]{P}X{P}{CIMPVW}, where [XY] denotes either X or Y and {XY} denotes neither X nor Y. We further verify the validity of the motif by site-directed mutagenesis and show that substrate binding by Ydj1 requires recognition of this motif. A yeast proteome screen revealed that many proteins contain more than one stretch of residues that contain the motif and are separated by varying numbers of amino acids. In light of our results, we propose a 2-site peptide-binding model and a plausible mechanism of peptide presentation by Ydj1p to the chaperones of the Hsp70 family. Based on our results, and given that Ydj1p and its human ortholog Hdj2 are functionally interchangeable, we hypothesize that our results can be extended to understanding human diseases.

Original languageEnglish (US)
Pages (from-to)11073-11078
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number27
DOIs
StatePublished - Jul 7 2009

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Peptides
Proteins
Proteostasis Deficiencies
Yeasts
Protein Refolding
Molecular Chaperones
Poisons
Consensus Sequence
Proteome
Site-Directed Mutagenesis
Binding Sites
Escherichia coli
Amino Acids

All Science Journal Classification (ASJC) codes

  • General

Cite this

Kota, Pradeep ; Summers, Daniel W. ; Ren, Hong Yu ; Cyr, Douglas M. ; Dokholyan, Nikolay V. / Identification of a consensus motif in substrates bound by a Type I Hsp40. In: Proceedings of the National Academy of Sciences of the United States of America. 2009 ; Vol. 106, No. 27. pp. 11073-11078.
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Identification of a consensus motif in substrates bound by a Type I Hsp40. / Kota, Pradeep; Summers, Daniel W.; Ren, Hong Yu; Cyr, Douglas M.; Dokholyan, Nikolay V.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 27, 07.07.2009, p. 11073-11078.

Research output: Contribution to journalArticle

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