Charged linker sequence modulates eukaryotic heat shock protein 90 (Hsp90) chaperone activity

Hsp90 is an essential and highly conserved modular molecular chaperone whose N and middle domains are separated by a disordered region termed the charged linker. Although its importance has been previously disregarded, because a minimal linker length is sufficient for Hsp90 activity, the evolutionar...

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Published in:	Proceedings of the National Academy of Sciences - PNAS 2012-02, Vol.109 (8), p.2937-2942
Main Authors:	Tsutsumi, Shinji, Mollapour, Mehdi, Prodromou, Chrisostomos, Lee, Chung-Tien, Panaretou, Barry, Yoshida, Soichiro, Mayer, Matthias P, Neckers, Leonard M
Format:	Article
Language:	eng
Subjects:	Adenosine triphosphatase Adenosine triphosphatases adenosinetriphosphatase Amides Amino Acid Sequence Amino acids Biological Sciences Deuterium - metabolism Eukaryotes eukaryotic cells Eukaryotic Cells - metabolism Evolutionary biology Heat shock proteins HSP90 Heat-Shock Proteins - chemistry HSP90 Heat-Shock Proteins - metabolism Humans Hydrogen Molecular Sequence Data Molecular structure Peptide Hydrolases - metabolism Plasmids Plasmodium Protein Binding Proteins Saccharomyces cerevisiae - metabolism Saccharomyces cerevisiae Proteins - chemistry Saccharomyces cerevisiae Proteins - metabolism Solvents Structure-Activity Relationship Viability Yeasts
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Summary:	Hsp90 is an essential and highly conserved modular molecular chaperone whose N and middle domains are separated by a disordered region termed the charged linker. Although its importance has been previously disregarded, because a minimal linker length is sufficient for Hsp90 activity, the evolutionary persistence of extensive charged linkers of divergent sequence in Hsp90 proteins of most eukaryotes remains unexplained. To examine this question further, we introduced human and plasmodium native and length-matched artificial linkers into yeast Hsp90. After evaluating ATPase activity and biophysical characteristics in vitro, and chaperone function in vivo, we conclude that linker sequence affects Hsp90 function, cochaperone interaction, and conformation. We propose that the charged linker, in addition to providing the flexibility necessary for Hsp90 domain rearrangements—likely its original purpose—has evolved in eukaryotes to serve as a rheostat for the Hsp90 chaperone machine.
ISSN:	0027-8424 1091-6490