Tah1 helix-swap dimerization prevents mixed Hsp90 co-chaperone complexes

Area of Science:

• Molecular Biology
• Protein Structure
• Biochemistry

Background:

• Heat shock protein 90 (Hsp90) is a molecular chaperone essential for the assembly and regulation of diverse client proteins.
• Co-chaperone adaptors, such as Tah1, link client proteins to the Hsp90 machinery.
• Tah1 possesses an atypical tetratricopeptide repeat (TPR) domain structure, comprising only five α-helices instead of the usual seven.

Purpose of the Study:

• To elucidate the structural basis for Tah1's function in Hsp90-mediated protein regulation.
• To understand how Tah1's unique TPR domain structure influences its interaction with Hsp90.
• To explain the mechanism by which Tah1 prevents the formation of aberrant co-chaperone complexes.

Main Methods:

• Crystal structure determination of Tah1 in complex with the Hsp90 MEEVD peptide.
• Analysis of Tah1's oligomeric state in solution.
• Comparative structural analysis of Tah1 with other TPR domain proteins.

Main Results:

• The crystal structure reveals a helix swap involving the fifth α-helix of Tah1 between adjacent molecules, leading to dimerization.
• Tah1 dimerization reconstitutes a canonical TPR binding site, restoring the normal binding environment for the Hsp90 MEEVD motif.
• The dimeric structure of Tah1 explains its predominantly monomeric behavior in solution and its ability to exclude other TPR domain proteins.

Conclusions:

• Tah1 functions as a dimer to bind Hsp90, creating a functional TPR binding site similar to canonical seven-helix TPR domains.
• Tah1 dimerization is crucial for its role in regulating Hsp90 client protein assembly and preventing the formation of inappropriate mixed co-chaperone complexes.