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

Nicholas McCaul; Matthias Quandte; Ilja Bontjer; Guus van Zadelhoff; Aafke Land; Ema T. Crooks; James M. Binley; Rogier W. Sanders; Ineke Braakman

doi:10.1016/j.celrep.2021.109646

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

Nicholas McCaul, Matthias Quandte, Ilja Bontjer, Guus van Zadelhoff, Aafke Land, Ema T. Crooks, James M. Binley, Rogier W. Sanders, Ineke Braakman^*

^*Corresponding author for this work

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

Abstract

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.

Original language	English
Article number	109646
Pages (from-to)	1-21
Journal	Cell Reports
Volume	36
Issue number	9
DOIs	https://doi.org/10.1016/j.celrep.2021.109646
Publication status	Published - 31 Aug 2021

Bibliographical note

Funding Information:
We would like to thank members of the Braakman-Van der Sluijs and Sanders labs for their fruitful discussions and insights—in particular, Peter van der Sluijs for critical reading of the manuscript and Joseline Houwman for critical reading of the manuscript and design of Figure 7 . This work was supported by grants from the Dutch Research Council (NWO)- Chemical Sciences 711.012.008 (I. Braakman, N.M., A.L., M.Q.), the European Union 7th framework program , ITN “Virus Entry” 235649 (I. Braakman, N.M., M.Q.), and the European Union’s Horizon 2020 research and innovation program under grant 681137 (R.W.S. and I. Bontjer). R.W.S. is a recipient of a Vici grant from the Dutch Research Council (NWO: 91818627 ).

Funding Information:
We would like to thank members of the Braakman-Van der Sluijs and Sanders labs for their fruitful discussions and insights?in particular, Peter van der Sluijs for critical reading of the manuscript and Joseline Houwman for critical reading of the manuscript and design of Figure 7. This work was supported by grants from the Dutch Research Council (NWO)- Chemical Sciences 711.012.008 (I. Braakman, N.M. A.L. M.Q.), the European Union 7th framework program, ITN ?Virus Entry? 235649 (I. Braakman, N.M. M.Q.), and the European Union's Horizon 2020 research and innovation program under grant 681137 (R.W.S. and I. Bontjer). R.W.S. is a recipient of a Vici grant from the Dutch Research Council (NWO: 91818627). Conceptualization, N.M. M.Q. and I. Braakman; methodology, N.M.; investigation, N.M. M.Q. I. Bontjer, and A.L.; writing ? original draft, N.M. M.Q. and I. Braakman; writing ? review & editing, N.M. M.Q. I. Bontjer, R.W.S. A.L. and I Braakman; funding acquisition, R.W.S. and I. Braakman. The authors declare no competing interests.

Publisher Copyright:
© 2021 The Authors

Funding

We would like to thank members of the Braakman-Van der Sluijs and Sanders labs for their fruitful discussions and insights—in particular, Peter van der Sluijs for critical reading of the manuscript and Joseline Houwman for critical reading of the manuscript and design of Figure 7 . This work was supported by grants from the Dutch Research Council (NWO)- Chemical Sciences 711.012.008 (I. Braakman, N.M., A.L., M.Q.), the European Union 7th framework program , ITN “Virus Entry” 235649 (I. Braakman, N.M., M.Q.), and the European Union’s Horizon 2020 research and innovation program under grant 681137 (R.W.S. and I. Bontjer). R.W.S. is a recipient of a Vici grant from the Dutch Research Council (NWO: 91818627 ). We would like to thank members of the Braakman-Van der Sluijs and Sanders labs for their fruitful discussions and insights?in particular, Peter van der Sluijs for critical reading of the manuscript and Joseline Houwman for critical reading of the manuscript and design of Figure 7. This work was supported by grants from the Dutch Research Council (NWO)- Chemical Sciences 711.012.008 (I. Braakman, N.M. A.L. M.Q.), the European Union 7th framework program, ITN ?Virus Entry? 235649 (I. Braakman, N.M. M.Q.), and the European Union's Horizon 2020 research and innovation program under grant 681137 (R.W.S. and I. Bontjer). R.W.S. is a recipient of a Vici grant from the Dutch Research Council (NWO: 91818627). Conceptualization, N.M. M.Q. and I. Braakman; methodology, N.M.; investigation, N.M. M.Q. I. Bontjer, and A.L.; writing ? original draft, N.M. M.Q. and I. Braakman; writing ? review & editing, N.M. M.Q. I. Bontjer, R.W.S. A.L. and I Braakman; funding acquisition, R.W.S. and I. Braakman. The authors declare no competing interests.

Keywords

disulfide bond
disulfide isomerization
endoplasmic reticulum
envelope glycoprotein
gp120
HIV-1
membrane tethering
protein folding
redox-active cysteine
signal peptide

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Cite this

@article{62a23776e397415eb52dd021794c65e0,

title = "Intramolecular quality control: HIV-1 envelope gp160 signal-peptide cleavage as a functional folding checkpoint",

abstract = "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.",

keywords = "disulfide bond, disulfide isomerization, endoplasmic reticulum, envelope glycoprotein, gp120, HIV-1, membrane tethering, protein folding, redox-active cysteine, signal peptide",

author = "Nicholas McCaul and Matthias Quandte and Ilja Bontjer and {van Zadelhoff}, Guus and Aafke Land and Crooks, {Ema T.} and Binley, {James M.} and Sanders, {Rogier W.} and Ineke Braakman",

note = "Funding Information: We would like to thank members of the Braakman-Van der Sluijs and Sanders labs for their fruitful discussions and insights—in particular, Peter van der Sluijs for critical reading of the manuscript and Joseline Houwman for critical reading of the manuscript and design of Figure 7 . This work was supported by grants from the Dutch Research Council (NWO)- Chemical Sciences 711.012.008 (I. Braakman, N.M., A.L., M.Q.), the European Union 7th framework program , ITN “Virus Entry” 235649 (I. Braakman, N.M., M.Q.), and the European Union{\textquoteright}s Horizon 2020 research and innovation program under grant 681137 (R.W.S. and I. Bontjer). R.W.S. is a recipient of a Vici grant from the Dutch Research Council (NWO: 91818627 ). Funding Information: We would like to thank members of the Braakman-Van der Sluijs and Sanders labs for their fruitful discussions and insights?in particular, Peter van der Sluijs for critical reading of the manuscript and Joseline Houwman for critical reading of the manuscript and design of Figure 7. This work was supported by grants from the Dutch Research Council (NWO)- Chemical Sciences 711.012.008 (I. Braakman, N.M. A.L. M.Q.), the European Union 7th framework program, ITN ?Virus Entry? 235649 (I. Braakman, N.M. M.Q.), and the European Union's Horizon 2020 research and innovation program under grant 681137 (R.W.S. and I. Bontjer). R.W.S. is a recipient of a Vici grant from the Dutch Research Council (NWO: 91818627). Conceptualization, N.M. M.Q. and I. Braakman; methodology, N.M.; investigation, N.M. M.Q. I. Bontjer, and A.L.; writing ? original draft, N.M. M.Q. and I. Braakman; writing ? review & editing, N.M. M.Q. I. Bontjer, R.W.S. A.L. and I Braakman; funding acquisition, R.W.S. and I. Braakman. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021 The Authors",

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doi = "10.1016/j.celrep.2021.109646",

language = "English",

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T1 - Intramolecular quality control

T2 - HIV-1 envelope gp160 signal-peptide cleavage as a functional folding checkpoint

AU - McCaul, Nicholas

AU - Quandte, Matthias

AU - Bontjer, Ilja

AU - van Zadelhoff, Guus

AU - Land, Aafke

AU - Crooks, Ema T.

AU - Binley, James M.

AU - Sanders, Rogier W.

AU - Braakman, Ineke

N1 - Funding Information: We would like to thank members of the Braakman-Van der Sluijs and Sanders labs for their fruitful discussions and insights—in particular, Peter van der Sluijs for critical reading of the manuscript and Joseline Houwman for critical reading of the manuscript and design of Figure 7 . This work was supported by grants from the Dutch Research Council (NWO)- Chemical Sciences 711.012.008 (I. Braakman, N.M., A.L., M.Q.), the European Union 7th framework program , ITN “Virus Entry” 235649 (I. Braakman, N.M., M.Q.), and the European Union’s Horizon 2020 research and innovation program under grant 681137 (R.W.S. and I. Bontjer). R.W.S. is a recipient of a Vici grant from the Dutch Research Council (NWO: 91818627 ). Funding Information: We would like to thank members of the Braakman-Van der Sluijs and Sanders labs for their fruitful discussions and insights?in particular, Peter van der Sluijs for critical reading of the manuscript and Joseline Houwman for critical reading of the manuscript and design of Figure 7. This work was supported by grants from the Dutch Research Council (NWO)- Chemical Sciences 711.012.008 (I. Braakman, N.M. A.L. M.Q.), the European Union 7th framework program, ITN ?Virus Entry? 235649 (I. Braakman, N.M. M.Q.), and the European Union's Horizon 2020 research and innovation program under grant 681137 (R.W.S. and I. Bontjer). R.W.S. is a recipient of a Vici grant from the Dutch Research Council (NWO: 91818627). Conceptualization, N.M. M.Q. and I. Braakman; methodology, N.M.; investigation, N.M. M.Q. I. Bontjer, and A.L.; writing ? original draft, N.M. M.Q. and I. Braakman; writing ? review & editing, N.M. M.Q. I. Bontjer, R.W.S. A.L. and I Braakman; funding acquisition, R.W.S. and I. Braakman. The authors declare no competing interests. Publisher Copyright: © 2021 The Authors

PY - 2021/8/31

Y1 - 2021/8/31

N2 - 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.

AB - 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.

KW - disulfide bond

KW - disulfide isomerization

KW - endoplasmic reticulum

KW - envelope glycoprotein

KW - gp120

KW - HIV-1

KW - membrane tethering

KW - protein folding

KW - redox-active cysteine

KW - signal peptide

U2 - 10.1016/j.celrep.2021.109646

DO - 10.1016/j.celrep.2021.109646

M3 - Article

C2 - 34469718

AN - SCOPUS:85114020506

SN - 2211-1247

VL - 36

SP - 1

EP - 21

JO - Cell Reports

JF - Cell Reports

IS - 9

M1 - 109646

ER -

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

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

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