PDBsum entry 2bug

Hydrolase

PDB id: 2bug

Contents

Protein chain

131 a.a. *

Ligands

ACE-MET-GLU-GLU-VAL-ASP

* Residue conservation analysis

PDB id:

2bug

Name:

Hydrolase

Title:

Solution structure of the tpr domain from protein phosphatase 5 in complex with hsp90 derived peptide

Structure:

Serine/threonine protein phosphatase 5. Chain: a. Fragment: tetratricopeptide domain, residues 19-147. Synonym: protein phosphatase 5, pp5, ppt. Engineered: yes. Mutation: yes. Other_details: residues 19-147 with n-terminal his-tag. Hsp90. Chain: b.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 469008. Synthetic: yes. Organism_taxid: 9606

NMR struc:

19 models

Authors:

M.J.Cliff,R.Harris,D.Barford,J.E.Ladbury,M.A.Williams

Key ref:

M.J.Cliff et al. (2006). Conformational diversity in the TPR domain-mediated interaction of protein phosphatase 5 with Hsp90. Structure, 14, 415-426. PubMed id: 16531226 DOI: 10.1016/j.str.2005.12.009

Date:

13-Jun-05 Release date: 16-Mar-06

Protein chain

P53041  (PPP5_HUMAN) -  Serine/threonine-protein phosphatase 5 from Homo sapiens

Seq: 499 a.a.

Struc: 131 a.a.*

* PDB and UniProt seqs differ at 3 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.3.1.3.16 - protein-serine/threonine phosphatase.
• Reaction:
  1. O-phospho-L-seryl-[protein] + H2O = L-seryl-[protein] + phosphate
  2. O-phospho-L-threonyl-[protein] + H2O = L-threonyl-[protein] + phosphate

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1016/j.str.2005.12.009

Structure 14:415-426 (2006)

PubMed id: 16531226

Conformational diversity in the TPR domain-mediated interaction of protein phosphatase 5 with Hsp90.

M.J.Cliff, R.Harris, D.Barford, J.E.Ladbury, M.A.Williams.

ABSTRACT

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.

Selected figure(s)

Figure 3.
Figure 3. Structural and Dynamic Features of the Hsp90 Peptide Binding Site
(A) Conserved polar two-carboxylate clamp residues are shown in purple; additional residues consistently involved in ligand binding are shown in pale blue. Residues that are physically distinct between Hop and Ppp5 and whose variation is responsible for the different binding modes of the Hsp90 peptide between those complexes are shown in gray.
(B) Extent of side chain assignment shown on the surface of the TPR domain (rotated 90° with respect to [A]). Unassigned resonances are shown in red, assigned resonances are shown in green, and the peptide is shown as a stick model. The absence of side chain resonances from the spectra suggests that the affected chemical groups are undergoing significant microsecond to millisecond timescale motion.

Figure 7.
Figure 7. Implications of the Structure for Relief of Autoinibition of Ppp5
Structures of the Hsp90 peptide bound TPR domains from Ppp5-TPR and Hop-TPR2A are superimposed on the structure of the autoinhibited form of Ppp5. The probable directions of continuation of the Hsp90 polypeptide chain are indicated by the dashed lines. A model based on the Hop structure suggested direct displacement of the αJ helix, which forms part of the autoinhibitory interface. The actual structure of the Ppp5-TPR/peptide complex suggests that such competition does not occur, and that displacement of α7 of the domain as a result of ligand binding instead disrupts the αJ interaction.

The above figures are reprinted by permission from Cell Press: Structure (2006, 14, 415-426) copyright 2006.

Figures were selected by the author.

Author's comment

A substantial number of mutli-domain proteins recognise the highly negatively charged EEVD motifs at the C-termini of the molecular chaperones Hsp70 and Hsp90 using a TPR domain. Early structures of examples of these protein-protein recognition interfaces showed extended conformations of the bound peptide which enable selective interaction of any particular TPR domain with either Hsp70 or Hsp90 termini via contacts with residues preceding the common EEVD motif. This first solution structure of TPR domain - MEEVD peptide interaction is derived from protein phosphatase 5 which interacts with both chaperones, and here we see a smaller and highly dynamic recognition interface which nevertheless binds with higher affinity than other TPR domains.
NMR measurements also show that the TPR domain itself is quite flexible and binding of the Hsp90/Hsp70-derived peptide appears to make the structure more compact. Compared with the structure of the isolated intact phosphatase (PDB:1wao), this conformational change suggests an allosteric mechanism for regulation of phosphatase activity by chaperone binding.
Mark A. Williams