Intramolecular quality control: HIV-1 envelope gp160 signal-peptide cleavage as a functional folding checkpoint.

Autor:	McCaul N; Cellular Protein Chemistry, Bijvoet Center for Biomolecular Research, Science4Life, Faculty of Science, Utrecht University, Padualaan 8, 3584 Utrecht, the Netherlands., Quandte M; Cellular Protein Chemistry, Bijvoet Center for Biomolecular Research, Science4Life, Faculty of Science, Utrecht University, Padualaan 8, 3584 Utrecht, the Netherlands., Bontjer I; Department of Medical Microbiology, Amsterdam UMC, University of Amsterdam, Amsterdam Institute for Infection and Immunity, 1105 Amsterdam, the Netherlands., van Zadelhoff G; Cellular Protein Chemistry, Bijvoet Center for Biomolecular Research, Science4Life, Faculty of Science, Utrecht University, Padualaan 8, 3584 Utrecht, the Netherlands., Land A; Cellular Protein Chemistry, Bijvoet Center for Biomolecular Research, Science4Life, Faculty of Science, Utrecht University, Padualaan 8, 3584 Utrecht, the Netherlands., Crooks ET; San Diego Biomedical Research Institute, 10865 Road to the Cure #100, San Diego, CA, USA., Binley JM; San Diego Biomedical Research Institute, 10865 Road to the Cure #100, San Diego, CA, USA., Sanders RW; Department of Medical Microbiology, Amsterdam UMC, University of Amsterdam, Amsterdam Institute for Infection and Immunity, 1105 Amsterdam, the Netherlands; Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021, USA., Braakman I; Cellular Protein Chemistry, Bijvoet Center for Biomolecular Research, Science4Life, Faculty of Science, Utrecht University, Padualaan 8, 3584 Utrecht, the Netherlands. Electronic address: i.braakman@uu.nl.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2021 Aug 31; Vol. 36 (9), pp. 109646.
DOI:	10.1016/j.celrep.2021.109646
Abstrakt:	Removal of the membrane-tethering signal peptides that target secretory proteins to the endoplasmic reticulum is a prerequisite for proper folding. While generally thought to be removed co-translationally, we report two additional post-targeting functions for the HIV-1 gp120 signal peptide, which remains attached until gp120 folding triggers its removal. First, the signal peptide improves folding fidelity by enhancing conformational plasticity of gp120 by driving disulfide isomerization through a redox-active cysteine. Simultaneously, the signal peptide delays folding by tethering the N terminus to the membrane, until assembly with the C terminus. Second, its carefully timed cleavage represents intramolecular quality control and ensures release of (only) natively folded gp120. Postponed cleavage and the redox-active cysteine are both highly conserved and important for viral fitness. Considering the ∼15% proteins with signal peptides and the frequency of N-to-C contacts in protein structures, these regulatory roles of signal peptides are bound to be more common in secretory-protein biogenesis. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu