An Allosteric Interaction Network Promotes Conformation State-Dependent Eviction of the Nas6 Assembly Chaperone from Nascent 26S Proteasomes

Antonia A. Nemec; Anna K. Peterson; Jennifer L. Warnock; Randi G. Reed; Robert J. Tomko

doi:10.1016/j.celrep.2018.12.042

An Allosteric Interaction Network Promotes Conformation State-Dependent Eviction of the Nas6 Assembly Chaperone from Nascent 26S Proteasomes

Antonia A. Nemec
, Anna K. Peterson
, Jennifer L. Warnock
, Randi G. Reed
, Robert J. Tomko

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

14 Scopus citations

Abstract

The 26S proteasome is the central ATP-dependent protease in eukaryotes and is essential for organismal health. Proteasome assembly is mediated by several dedicated, evolutionarily conserved chaperone proteins. These chaperones associate transiently with assembly intermediates but are absent from mature proteasomes. Chaperone eviction upon completion of proteasome assembly is necessary for normal proteasome function, but how they are released remains unresolved. Here, we demonstrate that the Nas6 assembly chaperone, homolog of the human oncogene gankyrin, is evicted from nascent proteasomes during completion of assembly via a conformation-specific allosteric interaction of the Rpn5 subunit with the proteasomal ATPase ring. Subsequent ATP binding by the ATPase subunit Rpt3 promotes conformational remodeling of the ATPase ring that evicts Nas6 from the nascent proteasome. Our study demonstrates how assembly-coupled allosteric signals promote chaperone eviction and provides a framework for understanding the eviction of other chaperones from this biomedically important molecular machine.

Original language	English
Pages (from-to)	483-495.e5
Journal	Cell Reports
Volume	26
Issue number	2
DOIs	https://doi.org/10.1016/j.celrep.2018.12.042
State	Published - Jan 8 2019
Externally published	Yes

Funding

The authors thank Mark Hochstrasser, William P. Tansey, and Andreas Matouschek for strains and reagents; the Florida State University College of Medicine Translational Science Laboratory for mass spectrometry service; Beth Stroupe for advice on quantifying steric clash; and the Florida State University yeast community for helpful discussions. This work was supported by start-up funds from Florida State University College of Medicine and NIH grant 1R01GM118600 (to R.J.T.). The authors thank Mark Hochstrasser, William P. Tansey, and Andreas Matouschek for strains and reagents; the Florida State University College of Medicine Translational Science Laboratory for mass spectrometry service; Beth Stroupe for advice on quantifying steric clash; and the Florida State University yeast community for helpful discussions. This work was supported by start-up funds from Florida State University College of Medicine and NIH grant 1R01GM118600 (to R.J.T.).

Keywords

Nas6
assembly
gankyrin
macromolecular complex
oncogene
proteasome
proteolysis
ubiquitin

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10.1016/j.celrep.2018.12.042

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title = "An Allosteric Interaction Network Promotes Conformation State-Dependent Eviction of the Nas6 Assembly Chaperone from Nascent 26S Proteasomes",

abstract = "The 26S proteasome is the central ATP-dependent protease in eukaryotes and is essential for organismal health. Proteasome assembly is mediated by several dedicated, evolutionarily conserved chaperone proteins. These chaperones associate transiently with assembly intermediates but are absent from mature proteasomes. Chaperone eviction upon completion of proteasome assembly is necessary for normal proteasome function, but how they are released remains unresolved. Here, we demonstrate that the Nas6 assembly chaperone, homolog of the human oncogene gankyrin, is evicted from nascent proteasomes during completion of assembly via a conformation-specific allosteric interaction of the Rpn5 subunit with the proteasomal ATPase ring. Subsequent ATP binding by the ATPase subunit Rpt3 promotes conformational remodeling of the ATPase ring that evicts Nas6 from the nascent proteasome. Our study demonstrates how assembly-coupled allosteric signals promote chaperone eviction and provides a framework for understanding the eviction of other chaperones from this biomedically important molecular machine.",

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author = "Nemec, \{Antonia A.\} and Peterson, \{Anna K.\} and Warnock, \{Jennifer L.\} and Reed, \{Randi G.\} and Tomko, \{Robert J.\}",

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year = "2019",

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doi = "10.1016/j.celrep.2018.12.042",

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AU - Peterson, Anna K.

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AU - Reed, Randi G.

AU - Tomko, Robert J.

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Y1 - 2019/1/8

N2 - The 26S proteasome is the central ATP-dependent protease in eukaryotes and is essential for organismal health. Proteasome assembly is mediated by several dedicated, evolutionarily conserved chaperone proteins. These chaperones associate transiently with assembly intermediates but are absent from mature proteasomes. Chaperone eviction upon completion of proteasome assembly is necessary for normal proteasome function, but how they are released remains unresolved. Here, we demonstrate that the Nas6 assembly chaperone, homolog of the human oncogene gankyrin, is evicted from nascent proteasomes during completion of assembly via a conformation-specific allosteric interaction of the Rpn5 subunit with the proteasomal ATPase ring. Subsequent ATP binding by the ATPase subunit Rpt3 promotes conformational remodeling of the ATPase ring that evicts Nas6 from the nascent proteasome. Our study demonstrates how assembly-coupled allosteric signals promote chaperone eviction and provides a framework for understanding the eviction of other chaperones from this biomedically important molecular machine.

AB - The 26S proteasome is the central ATP-dependent protease in eukaryotes and is essential for organismal health. Proteasome assembly is mediated by several dedicated, evolutionarily conserved chaperone proteins. These chaperones associate transiently with assembly intermediates but are absent from mature proteasomes. Chaperone eviction upon completion of proteasome assembly is necessary for normal proteasome function, but how they are released remains unresolved. Here, we demonstrate that the Nas6 assembly chaperone, homolog of the human oncogene gankyrin, is evicted from nascent proteasomes during completion of assembly via a conformation-specific allosteric interaction of the Rpn5 subunit with the proteasomal ATPase ring. Subsequent ATP binding by the ATPase subunit Rpt3 promotes conformational remodeling of the ATPase ring that evicts Nas6 from the nascent proteasome. Our study demonstrates how assembly-coupled allosteric signals promote chaperone eviction and provides a framework for understanding the eviction of other chaperones from this biomedically important molecular machine.

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KW - assembly

KW - gankyrin

KW - macromolecular complex

KW - oncogene

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KW - proteolysis

KW - ubiquitin

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An Allosteric Interaction Network Promotes Conformation State-Dependent Eviction of the Nas6 Assembly Chaperone from Nascent 26S Proteasomes

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