Conformational diversity in the TPR domain-mediated interaction of protein phosphatase 5 with Hsp90.
Protein phosphatase 5 (Ppp5) is one of several proteins that bind to the Hsp90 chaperone via a tetratricopeptide repeat (TPR) domain. We report the solution structure of a complex of the TPR domain of Ppp5 with the C-terminal pentapeptide of Hsp90. This structure has the "two-carboxylate clamp" mechanism of peptide binding first seen in the Hop-TPR domain complexes with Hsp90 and Hsp70 peptides. However, NMR data reveal that the Ppp5 clamp is highly dynamic, and that there are multiple modes of peptide binding and mobility throughout the complex. Although this interaction is of very high affinity, relatively few persistent contacts are found between the peptide and the Ppp5-TPR domain, thus explaining its promiscuity in binding both Hsp70 and Hsp90 in vivo. We consider the possible implications of this dynamic structure for the mechanism of relief of autoinhibition in Ppp5 and for the mechanisms of TPR-mediated recognition of Hsp90 by other proteins.
Cliff
Matthew J
MJ
Department of Biochemistry and Molecular Biology, University College London, Darwin Building, Gower Street, London WC1E 6BT, United Kingdom.
Harris
Richard
R
Barford
David
D
Ladbury
John E
JE
Williams
Mark A
MA
D000595:Amino Acid Sequence; D001665:Binding Sites; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry* / Q000235:genetics; D008024:Ligands; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry* / Q000235:genetics; D010455:Peptides / Q000737:chemistry; D010749:Phosphoprotein Phosphatases / Q000737:chemistry* / Q000235:genetics; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D020449:Repetitive Sequences, Amino Acid; D017386:Sequence Homology, Amino Acid; D014867:Water / Q000737:chemistry
D018841:HSP90 Heat-Shock Proteins; D008024:Ligands; D009687:Nuclear Proteins; D010455:Peptides; D014867:Water; D010749:Phosphoprotein Phosphatases; C089641:protein phosphatase 5