Deviation of the typical AAA substrate-threading pore prevents fatal protein degradation in yeast Cdc48

Abstract Yeast Cdc48 is a well-conserved, essential chaperone of ATPases associated with diverse cellular activity (AAA) proteins, which recognizes substrate proteins and modulates their conformations to carry out many cellular processes. However, the fundamental mechanisms underlying the diverse pi...

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Autores principales:	Masatoshi Esaki, Md. Tanvir Islam, Naoki Tani, Teru Ogura
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ecb31813bdce4930a00be7fc61b0001b
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spelling	oai:doaj.org-article:ecb31813bdce4930a00be7fc61b0001b2021-12-02T12:30:25ZDeviation of the typical AAA substrate-threading pore prevents fatal protein degradation in yeast Cdc4810.1038/s41598-017-05806-y2045-2322https://doaj.org/article/ecb31813bdce4930a00be7fc61b0001b2017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-05806-yhttps://doaj.org/toc/2045-2322Abstract Yeast Cdc48 is a well-conserved, essential chaperone of ATPases associated with diverse cellular activity (AAA) proteins, which recognizes substrate proteins and modulates their conformations to carry out many cellular processes. However, the fundamental mechanisms underlying the diverse pivotal roles of Cdc48 remain unknown. Almost all AAA proteins form a ring-shaped structure with a conserved aromatic amino acid residue that is essential for proper function. The threading mechanism hypothesis suggests that this residue guides the intrusion of substrate proteins into a narrow pore of the AAA ring, thereby becoming unfolded. By contrast, the aromatic residue in one of the two AAA rings of Cdc48 has been eliminated through evolution. Here, we show that artificial retrieval of this aromatic residue in Cdc48 is lethal, and essential features to support the threading mechanism are required to exhibit the lethal phenotype. In particular, genetic and biochemical analyses of the Cdc48 lethal mutant strongly suggested that when in complex with the 20S proteasome, essential proteins are abnormally forced to thread through the Cdc48 pore to become degraded, which was not detected in wild-type Cdc48. Thus, the widely applicable threading model is less effective for wild-type Cdc48; rather, Cdc48 might function predominantly through an as-yet-undetermined mechanism.Masatoshi EsakiMd. Tanvir IslamNaoki TaniTeru OguraNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Masatoshi Esaki Md. Tanvir Islam Naoki Tani Teru Ogura Deviation of the typical AAA substrate-threading pore prevents fatal protein degradation in yeast Cdc48
description	Abstract Yeast Cdc48 is a well-conserved, essential chaperone of ATPases associated with diverse cellular activity (AAA) proteins, which recognizes substrate proteins and modulates their conformations to carry out many cellular processes. However, the fundamental mechanisms underlying the diverse pivotal roles of Cdc48 remain unknown. Almost all AAA proteins form a ring-shaped structure with a conserved aromatic amino acid residue that is essential for proper function. The threading mechanism hypothesis suggests that this residue guides the intrusion of substrate proteins into a narrow pore of the AAA ring, thereby becoming unfolded. By contrast, the aromatic residue in one of the two AAA rings of Cdc48 has been eliminated through evolution. Here, we show that artificial retrieval of this aromatic residue in Cdc48 is lethal, and essential features to support the threading mechanism are required to exhibit the lethal phenotype. In particular, genetic and biochemical analyses of the Cdc48 lethal mutant strongly suggested that when in complex with the 20S proteasome, essential proteins are abnormally forced to thread through the Cdc48 pore to become degraded, which was not detected in wild-type Cdc48. Thus, the widely applicable threading model is less effective for wild-type Cdc48; rather, Cdc48 might function predominantly through an as-yet-undetermined mechanism.
format	article
author	Masatoshi Esaki Md. Tanvir Islam Naoki Tani Teru Ogura
author_facet	Masatoshi Esaki Md. Tanvir Islam Naoki Tani Teru Ogura
author_sort	Masatoshi Esaki
title	Deviation of the typical AAA substrate-threading pore prevents fatal protein degradation in yeast Cdc48
title_short	Deviation of the typical AAA substrate-threading pore prevents fatal protein degradation in yeast Cdc48
title_full	Deviation of the typical AAA substrate-threading pore prevents fatal protein degradation in yeast Cdc48
title_fullStr	Deviation of the typical AAA substrate-threading pore prevents fatal protein degradation in yeast Cdc48
title_full_unstemmed	Deviation of the typical AAA substrate-threading pore prevents fatal protein degradation in yeast Cdc48
title_sort	deviation of the typical aaa substrate-threading pore prevents fatal protein degradation in yeast cdc48
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/ecb31813bdce4930a00be7fc61b0001b
work_keys_str_mv	AT masatoshiesaki deviationofthetypicalaaasubstratethreadingporepreventsfatalproteindegradationinyeastcdc48 AT mdtanvirislam deviationofthetypicalaaasubstratethreadingporepreventsfatalproteindegradationinyeastcdc48 AT naokitani deviationofthetypicalaaasubstratethreadingporepreventsfatalproteindegradationinyeastcdc48 AT teruogura deviationofthetypicalaaasubstratethreadingporepreventsfatalproteindegradationinyeastcdc48
_version_	1718394431247220736

Deviation of the typical AAA substrate-threading pore prevents fatal protein degradation in yeast Cdc48

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