Abstract
Mammals have two cysteine- and histidine-rich domain (CHORD)-containing Hsp90 cochaperones, Chp-1 and melusin, which are homologs of plant Rar1. It has been shown previously that Rar1 CHORD directly interacts with ADP bound to the nucleotide pocket of Hsp90. Here, we report that ADP and ATP can bind to Hsp90 cochaperones Chp-1 and PP5, inducing their conformational changes. Furthermore, we demonstrate that Chp-1 and melusin can interact with cochaperones PP5 and Sgt1 and with each other in an ATP-dependent manner. Based on the known structure of the Rar1-Hsp90 complex, His-186 has been identified as an important residue of Chp-1 for ADP/ATP binding. His-186 is necessary for the nucleotide-dependent interaction of Chp-1 not only with Hsp90 but also with Sgt1. In addition, Ca(2+), which is known to bind to melusin, enhances the interactions of melusin with Hsp90 and Sgt1. Furthermore, melusin acquires the ADP preference for Hsp90 binding in the presence of Ca(2+). Our newly discovered nucleotide-dependent interactions between cochaperones might provide additional complexity to the dynamics of the Hsp90 chaperone system, also suggesting potential Hsp90-independent roles for these cochaperones.
Highlights
Hsp90 cochaperones are regulating interactors of Hsp90, but interactions between themselves are not well known
These results suggest that Hsp90 cochaperones retain the property of nucleotide-dependent interaction with Hsp90 and with themselves, implying that each component of the Hsp90 chaperone machinery may participate in the dynamic assembly of multiple complexes depending on the cellular environment
Hsp90 Cochaperones Chp-1 and PP5, but Not Sgt1, Bind to ADP and ATP—The crystal structure of the complex of the plant Hsp90 N-terminal, Sgt1 CS, and Rar1 CHORD-II domains shows that Rar1 CHORD-II directly interacts with the ADP bound to the nucleotide pocket of the Hsp90 N-terminal domain [15]
Summary
Hsp cochaperones are regulating interactors of Hsp, but interactions between themselves are not well known. Chp-1 and melusin contain the additional C-terminal CS domain as well as the two conserved CHORDs [18] Both Chp-1 and melusin interact with Hsp, suggesting their potential roles as Hsp cochap-. Both Chp-1 and Sgt seem to be involved in mitosis, their genetic or physical connections in vivo remain elusive It is not known whether melusin and Chp-1 carry out these functions as Hsp cochaperones or as Hsp90-independent regulators. We show a regulatory role for Ca2ϩ in the melusin/Hsp and melusin/Sgt interactions These results suggest that Hsp cochaperones retain the property of nucleotide-dependent interaction with Hsp and with themselves, implying that each component of the Hsp chaperone machinery may participate in the dynamic assembly of multiple complexes depending on the cellular environment
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