Molecular Playground/Hsp70-Hsp90

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TPR1


Hsp70-Hsp90 Organizing Protein (Hop)

HoP is an adaptor protein that mediates the association of the molecular chaperones Hsp70 and Hsp90 as some proteins require their coordinated activities for folding and conformational regulation. Hsp90 receives its substrates from Hsp70 in a reaction that is critically dependent on HoP, but how HoP mediates this dual chaperone binding was unclear until structural studies of HoP were conducted. HoP is not a chaperone itself, and it is composed almost entirely of Tetra-trico-peptide repeat (TPR) domains. TPR motifs are defined as multiple repeats of 34 amino acids that share a degenerate consensus sequence consisting of a pattern of small and large hydrophobic amino acids, with no position being completely invariant. TPR domains are found in many proteins and often serve as interaction modules in multiprotein complexes. HoP is a 543 amino acid protein with 9 predicted TPR motifs, which are organized into 3 TPR domains: TPR1, TPR2A, and TPR2B.

TPR Domain 1 Structure

consists of 3 and is responsible for the interaction with the C terminus of Hsp70 (motifs are colored red, blue, and purple respectively, and the C-terminal capping helix is shown in green). Mutation studies showed that the binding of TPR1 to Hsp70 is dependent upon the interaction between the TPR1 domain and a 12-mer C-terminal peptide of Hsp70 (GSGSGPTIEEVD). Shown to the right is the crystallized TPR1 with its respective Hsp70 heptapeptide partner. TPR1 forms a cradle-like structure that accommodates the Hsp70 peptide in an extended conformation, and the peptide makes contact with only the sidechains of the helices in TPR1 that face the inner surface of the cradle. Additionally, a highly conserved anchors the EEVD peptide motif of Hsp70 to TPR1 (residues highlighted in orange).


References

1. D'Andrea, L. Regan, L. TiBS Review; 28:12. 2003

2. Scheufler, C. et. al. Cell; 101:199-210. 2000

3. Zeytuni, N. et. al. Cell Structure; 20. 2012

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Jill Graham, Michal Harel, Eric Martz, Carrie Morrison Penland

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