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Ste24: An Integral Membrane Protein Zinc Metalloprotease with Provocative Structure and Emergent Biology
Ste24, an integral membrane protein zinc metalloprotease, is found in every kingdom of eukaryotes. It was discovered approximately 20 years ago by yeast genetic screens identifying it as a factor responsible for processing the yeast mating a-factor pheromone. In animals, Ste24 processes prelamin A,...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Elsevier Ltd.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7172729/ https://www.ncbi.nlm.nih.gov/pubmed/32199981 http://dx.doi.org/10.1016/j.jmb.2020.03.016 |
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author | Goblirsch, Brandon R. Wiener, Michael C. |
author_facet | Goblirsch, Brandon R. Wiener, Michael C. |
author_sort | Goblirsch, Brandon R. |
collection | PubMed |
description | Ste24, an integral membrane protein zinc metalloprotease, is found in every kingdom of eukaryotes. It was discovered approximately 20 years ago by yeast genetic screens identifying it as a factor responsible for processing the yeast mating a-factor pheromone. In animals, Ste24 processes prelamin A, a component of the nuclear lamina; mutations in the human ortholog of Ste24 diminish its activity, giving rise to genetic diseases of accelerated aging (progerias). Additionally, lipodystrophy, acquired from the standard highly active antiretroviral therapy used to treat AIDS patients, likely results from off-target interactions of HIV (aspartyl) protease inhibitor drugs with Ste24. Ste24 possesses a novel “α-barrel” structure, consisting of a ring of seven transmembrane α-helices enclosing a large (> 12,000 Å(3)) interior volume that contains the active-site and substrate-binding region; this “membrane-interior reaction chamber” is unprecedented in integral membrane protein structures. Additionally, the surface of the membrane-interior reaction chamber possesses a strikingly large negative electrostatic surface potential, adding additional “functional mystery.” Recent publications implicate Ste24 as a key factor in several endoplasmic reticulum processes, including the unfolded protein response, a cellular stress response of the endoplasmic reticulum, and removal of misfolded proteins from the translocon. Ste24, with its provocative structure, enigmatic mechanism, and recently emergent new biological roles including “translocon unclogger” and (non-enyzmatic) broad-spectrum viral restriction factor, presents far differently than before 2016, when it was viewed as a “CAAX protease” responsible for cleavage of prenylated (farnesylated or geranylgeranylated) substrates. The emphasis of this review is on Ste24 of the “Post-CAAX-Protease Era.” |
format | Online Article Text |
id | pubmed-7172729 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Elsevier Ltd. |
record_format | MEDLINE/PubMed |
spelling | pubmed-71727292020-04-22 Ste24: An Integral Membrane Protein Zinc Metalloprotease with Provocative Structure and Emergent Biology Goblirsch, Brandon R. Wiener, Michael C. J Mol Biol Review Ste24, an integral membrane protein zinc metalloprotease, is found in every kingdom of eukaryotes. It was discovered approximately 20 years ago by yeast genetic screens identifying it as a factor responsible for processing the yeast mating a-factor pheromone. In animals, Ste24 processes prelamin A, a component of the nuclear lamina; mutations in the human ortholog of Ste24 diminish its activity, giving rise to genetic diseases of accelerated aging (progerias). Additionally, lipodystrophy, acquired from the standard highly active antiretroviral therapy used to treat AIDS patients, likely results from off-target interactions of HIV (aspartyl) protease inhibitor drugs with Ste24. Ste24 possesses a novel “α-barrel” structure, consisting of a ring of seven transmembrane α-helices enclosing a large (> 12,000 Å(3)) interior volume that contains the active-site and substrate-binding region; this “membrane-interior reaction chamber” is unprecedented in integral membrane protein structures. Additionally, the surface of the membrane-interior reaction chamber possesses a strikingly large negative electrostatic surface potential, adding additional “functional mystery.” Recent publications implicate Ste24 as a key factor in several endoplasmic reticulum processes, including the unfolded protein response, a cellular stress response of the endoplasmic reticulum, and removal of misfolded proteins from the translocon. Ste24, with its provocative structure, enigmatic mechanism, and recently emergent new biological roles including “translocon unclogger” and (non-enyzmatic) broad-spectrum viral restriction factor, presents far differently than before 2016, when it was viewed as a “CAAX protease” responsible for cleavage of prenylated (farnesylated or geranylgeranylated) substrates. The emphasis of this review is on Ste24 of the “Post-CAAX-Protease Era.” Elsevier Ltd. 2020-08-21 2020-03-19 /pmc/articles/PMC7172729/ /pubmed/32199981 http://dx.doi.org/10.1016/j.jmb.2020.03.016 Text en © 2020 Elsevier Ltd. All rights reserved. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. |
spellingShingle | Review Goblirsch, Brandon R. Wiener, Michael C. Ste24: An Integral Membrane Protein Zinc Metalloprotease with Provocative Structure and Emergent Biology |
title | Ste24: An Integral Membrane Protein Zinc Metalloprotease with Provocative Structure and Emergent Biology |
title_full | Ste24: An Integral Membrane Protein Zinc Metalloprotease with Provocative Structure and Emergent Biology |
title_fullStr | Ste24: An Integral Membrane Protein Zinc Metalloprotease with Provocative Structure and Emergent Biology |
title_full_unstemmed | Ste24: An Integral Membrane Protein Zinc Metalloprotease with Provocative Structure and Emergent Biology |
title_short | Ste24: An Integral Membrane Protein Zinc Metalloprotease with Provocative Structure and Emergent Biology |
title_sort | ste24: an integral membrane protein zinc metalloprotease with provocative structure and emergent biology |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7172729/ https://www.ncbi.nlm.nih.gov/pubmed/32199981 http://dx.doi.org/10.1016/j.jmb.2020.03.016 |
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