An Acetylation Site in the Middle Domain of Hsp90 Regulates Chaperone Function

Bradley T. Scroggins; Kenneth Robzyk; Dongxia Wang; Monica G. Marcu; Shinji Tsutsumi; Kristin Beebe; Robert J. Cotter; Sara Felts; David Toft; Larry Karnitz; Neal Rosen; Len Neckers

doi:10.1016/j.molcel.2006.12.008

An Acetylation Site in the Middle Domain of Hsp90 Regulates Chaperone Function

Bradley T. Scroggins, Kenneth Robzyk, Dongxia Wang, Monica G. Marcu, Shinji Tsutsumi, Kristin Beebe, Robert J. Cotter, Sara Felts, David Toft, Larry Karnitz, Neal Rosen, Len Neckers

Research output: Contribution to journal › Article › peer-review

307 Scopus citations

Abstract

Heat-shock protein 90 (Hsp90) chaperones a key subset of signaling proteins and is necessary for malignant transformation. Hsp90 is subject to an array of posttranslational modifications that affect its function, including acetylation. Histone deacetylase (HDAC) inhibitors and knockdown of HDAC6 induce Hsp90 acetylation and inhibit its activity. However, direct determination of the functional consequences of Hsp90 acetylation has awaited mapping of specific sites. We now demonstrate that Hsp90 K294 is acetylated. Mutational analysis of K294 shows that its acetylation status is a strong determinant of client protein and cochaperone binding. In yeast, Hsp90 mutants that cannot be acetylated at K294 have reduced viability and chaperone function compared to WT or to mutants that mimic constitutive acetylation. These data suggest that acetylation/deacetylation of K294 plays an important role in regulating the Hsp90 chaperone cycle.

Original language	English (US)
Pages (from-to)	151-159
Number of pages	9
Journal	Molecular cell
Volume	25
Issue number	1
DOIs	https://doi.org/10.1016/j.molcel.2006.12.008
State	Published - Jan 12 2007
Externally published	Yes

Keywords

PROTEINS

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1016/j.molcel.2006.12.008

Cite this

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title = "An Acetylation Site in the Middle Domain of Hsp90 Regulates Chaperone Function",

abstract = "Heat-shock protein 90 (Hsp90) chaperones a key subset of signaling proteins and is necessary for malignant transformation. Hsp90 is subject to an array of posttranslational modifications that affect its function, including acetylation. Histone deacetylase (HDAC) inhibitors and knockdown of HDAC6 induce Hsp90 acetylation and inhibit its activity. However, direct determination of the functional consequences of Hsp90 acetylation has awaited mapping of specific sites. We now demonstrate that Hsp90 K294 is acetylated. Mutational analysis of K294 shows that its acetylation status is a strong determinant of client protein and cochaperone binding. In yeast, Hsp90 mutants that cannot be acetylated at K294 have reduced viability and chaperone function compared to WT or to mutants that mimic constitutive acetylation. These data suggest that acetylation/deacetylation of K294 plays an important role in regulating the Hsp90 chaperone cycle.",

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author = "Scroggins, {Bradley T.} and Kenneth Robzyk and Dongxia Wang and Marcu, {Monica G.} and Shinji Tsutsumi and Kristin Beebe and Cotter, {Robert J.} and Sara Felts and David Toft and Larry Karnitz and Neal Rosen and Len Neckers",

note = "Funding Information: We thank M. Yoshida, W. Houry, D. Smith, S. Lindquist, E. Craig, and A. Caplan for their generosity in supplying plasmids and yeast strains, C. Patterson for supplying anti-CHIP antibody, and T.A.J. Haystead for supplying ATP-agarose. We are also grateful to Ed Mimnaugh and Wanping Xu for helpful discussions. This work was supported by the National Cancer Institute's Intramural Research Program. B.T.S. was supported in part by an NCI Director's Intramural Innovation Award. ",

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doi = "10.1016/j.molcel.2006.12.008",

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AU - Scroggins, Bradley T.

AU - Robzyk, Kenneth

AU - Wang, Dongxia

AU - Marcu, Monica G.

AU - Tsutsumi, Shinji

AU - Beebe, Kristin

AU - Cotter, Robert J.

AU - Felts, Sara

AU - Toft, David

AU - Karnitz, Larry

AU - Rosen, Neal

AU - Neckers, Len

N1 - Funding Information: We thank M. Yoshida, W. Houry, D. Smith, S. Lindquist, E. Craig, and A. Caplan for their generosity in supplying plasmids and yeast strains, C. Patterson for supplying anti-CHIP antibody, and T.A.J. Haystead for supplying ATP-agarose. We are also grateful to Ed Mimnaugh and Wanping Xu for helpful discussions. This work was supported by the National Cancer Institute's Intramural Research Program. B.T.S. was supported in part by an NCI Director's Intramural Innovation Award.

PY - 2007/1/12

Y1 - 2007/1/12

N2 - Heat-shock protein 90 (Hsp90) chaperones a key subset of signaling proteins and is necessary for malignant transformation. Hsp90 is subject to an array of posttranslational modifications that affect its function, including acetylation. Histone deacetylase (HDAC) inhibitors and knockdown of HDAC6 induce Hsp90 acetylation and inhibit its activity. However, direct determination of the functional consequences of Hsp90 acetylation has awaited mapping of specific sites. We now demonstrate that Hsp90 K294 is acetylated. Mutational analysis of K294 shows that its acetylation status is a strong determinant of client protein and cochaperone binding. In yeast, Hsp90 mutants that cannot be acetylated at K294 have reduced viability and chaperone function compared to WT or to mutants that mimic constitutive acetylation. These data suggest that acetylation/deacetylation of K294 plays an important role in regulating the Hsp90 chaperone cycle.

AB - Heat-shock protein 90 (Hsp90) chaperones a key subset of signaling proteins and is necessary for malignant transformation. Hsp90 is subject to an array of posttranslational modifications that affect its function, including acetylation. Histone deacetylase (HDAC) inhibitors and knockdown of HDAC6 induce Hsp90 acetylation and inhibit its activity. However, direct determination of the functional consequences of Hsp90 acetylation has awaited mapping of specific sites. We now demonstrate that Hsp90 K294 is acetylated. Mutational analysis of K294 shows that its acetylation status is a strong determinant of client protein and cochaperone binding. In yeast, Hsp90 mutants that cannot be acetylated at K294 have reduced viability and chaperone function compared to WT or to mutants that mimic constitutive acetylation. These data suggest that acetylation/deacetylation of K294 plays an important role in regulating the Hsp90 chaperone cycle.

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An Acetylation Site in the Middle Domain of Hsp90 Regulates Chaperone Function

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