Molecular Playground/Hsp70-Hsp90

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Hsp70-Hsp90 Organizing Protein (Hop)Hsp70-Hsp90 Organizing Protein (Hop)

Hop is an adaptor protein which 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 hand-off 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 domains 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 StructureTPR Domain 1 Structure

TPR1 consists of 3 TPR motifs and is responsible for the interaction with the C terminus of Hsp70. 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 peptide 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 two-carboxylate clamp anchors the EEVD peptide motif of Hsp70 to TPR1.

is an Endoplasmic Reticulum (ER) resident protein disulfide isomerase. It is a 793 amino acid multi-domain protein. It consists of an N-terminal that has been shown to bind to BIP, ER resident HSP70, four redox-active domains (displayed here in green) and their respective redox-active CXXC motifs labeled in red and two domains shown in yellow, which lack CXXC redox-active motifs.

ReferencesReferences

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