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          Institute: MPI für molekulare Physiologie     Collection: Sonstige wissenschaftliche Organisationseinheiten     Display Documents

ID: 6122.0, MPI für molekulare Physiologie / Sonstige wissenschaftliche Organisationseinheiten
Ligand discrimination by TPR domains. Relevance and selectivity of EEVD-recognition in Hsp70·Hop·Hsp90 complexes
Authors:Brinker, Achim; Scheufler, Clemens; Von der Mülbe, Florian; Fleckenstein, Burkhard; Herrmann, Christian; Jung, Günther; Moarefi, Ismail; Hartl, F. Ulrich
Research Context:protein-protein recognition
Date of Publication (YYYY-MM-DD):2002-05-31
Title of Journal:Journal of Biological Chemistry
Journal Abbrev.:J. Biol. Chem.
Issue / Number:22
Start Page:19265
End Page:19275
Sequence Number of Article:1
Review Status:Peer-review
Audience:Experts Only
Intended Educational Use:No
Abstract / Description:Protein-protein interaction modules containing so-called tetratricopeptide repeats (TPRs) mediate the assembly of Hsp70/Hsp90 multi-chaperone complexes. The TPR1 and TPR2A domains of the Hsp70/Hsp90 adapter protein p60/Hop specifically bind to short peptides corresponding to the C-terminal tails of Hsp70 and Hsp90, respectively, both of which contain the highly conserved sequence motif EEVD-COOH. Here, we quantitatively assessed the contribution of TPR-mediated peptide recognition to Hsp70.Hop.Hsp90 complex formation. The interaction of TPR2A with the C-terminal pentapeptide of Hsp90 (AMEVD) is identified as the core contact for Hop binding to Hsp90. (In peptide sequences, italics are used to highlight residues specific for Hsp70 or Hsp90.) In contrast, formation of the Hsp70.Hop complex depends not only on recognition of the C-terminal Hsp70 heptapeptide (PTIEEVD) by TPR1 but also on additional contacts between Hsp70 and Hop. The sequence motifs for TPR1 and TPR2A binding were defined by alanine scanning of the C-terminal octapeptides of Hsp70 and Hsp90 and by screening of combinatorial peptide libraries. Asp0 and Val-1 of the EEVD motif are identified as general anchor residues, but the highly conserved glutamates of the EEVD sequence, which are critical in Hsp90 binding by TPR2A, do not contribute appreciably to the interaction of Hsp70 with TPR1. Rather, TPR1 prefers hydrophobic amino acids in these positions. Moreover, the TPR domains display a pronounced tendency to interact preferentially with hydrophobic aliphatic and aromatic side chains in positions -4 and -6 of their respective peptide ligands. Ile-4 in Hsp70 and Met-4 in Hsp90 are most important in determining the specific binding of TPR1 and TPR2A, respecti
External Publication Status:published
Document Type:Article
Communicated by:Jürgen Block
Affiliations:MPI für molekulare Physiologie/Abteilung I - Strukturelle Biologie/AG Struktur-Funktions-Beziehungen: PD Dr. Christian Herrmann
External Affiliations:SiREEN, Am Klopferspitz 19, D-82512 Martinsried, Germany;
Max Planck Inst Biochem, Dept Cellular Biochem, D-85152 Martinsried, Germany;
Univ Tübingen, Inst Organ Chem, D-72076 Tubingen, Germany;
Identifiers:URL:http://www.jbc.org/cgi/reprint/277/22/19265.pdf [pdf version of this article]
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