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Structure and topology around the cleavage site regulate post-translational cleavage of the HIV-1 gp160 signal peptide

EL. Snapp, N. McCaul, M. Quandte, Z. Cabartova, I. Bontjer, C. Källgren, I. Nilsson, A. Land, G. von Heijne, RW. Sanders, I. Braakman,

. 2017 ; 6 (-) : . [pub] 20170728

Language English Country England, Great Britain

Document type Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc18024791

Like all other secretory proteins, the HIV-1 envelope glycoprotein gp160 is targeted to the endoplasmic reticulum (ER) by its signal peptide during synthesis. Proper gp160 folding in the ER requires core glycosylation, disulfide-bond formation and proline isomerization. Signal-peptide cleavage occurs only late after gp160 chain termination and is dependent on folding of the soluble subunit gp120 to a near-native conformation. We here detail the mechanism by which co-translational signal-peptide cleavage is prevented. Conserved residues from the signal peptide and residues downstream of the canonical cleavage site form an extended alpha-helix in the ER membrane, which covers the cleavage site, thus preventing cleavage. A point mutation in the signal peptide breaks the alpha helix allowing co-translational cleavage. We demonstrate that postponed cleavage of gp160 enhances functional folding of the molecule. The change to early cleavage results in decreased viral fitness compared to wild-type HIV.

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$a Like all other secretory proteins, the HIV-1 envelope glycoprotein gp160 is targeted to the endoplasmic reticulum (ER) by its signal peptide during synthesis. Proper gp160 folding in the ER requires core glycosylation, disulfide-bond formation and proline isomerization. Signal-peptide cleavage occurs only late after gp160 chain termination and is dependent on folding of the soluble subunit gp120 to a near-native conformation. We here detail the mechanism by which co-translational signal-peptide cleavage is prevented. Conserved residues from the signal peptide and residues downstream of the canonical cleavage site form an extended alpha-helix in the ER membrane, which covers the cleavage site, thus preventing cleavage. A point mutation in the signal peptide breaks the alpha helix allowing co-translational cleavage. We demonstrate that postponed cleavage of gp160 enhances functional folding of the molecule. The change to early cleavage results in decreased viral fitness compared to wild-type HIV.
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$a HIV obalový protein gp160 $x chemie $x metabolismus $7 D019302
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$a McCaul, Nicholas $u Cellular Protein Chemistry, Bijvoet Center for Biomolecular Research, Faculty of Science, Utrecht University, Utrecht, Netherlands.
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$a Quandte, Matthias $u Cellular Protein Chemistry, Bijvoet Center for Biomolecular Research, Faculty of Science, Utrecht University, Utrecht, Netherlands.
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$a Cabartova, Zuzana $u National Institute of Public Health, National Reference Laboratory for Viral Hepatitis, Prague, Czech Republic.
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$a Bontjer, Ilja $u Department of Medical Microbiology, Laboratory of Experimental Virology, Center for Infection and Immunity Amsterdam, Academic Medical Center, Amsterdam, Netherlands.
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$a Källgren, Carolina $u Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden. Science for Life Laboratory, Stockholm University, Solna, Sweden.
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$a Nilsson, IngMarie $u Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden. Science for Life Laboratory, Stockholm University, Solna, Sweden.
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$a Land, Aafke $u Cellular Protein Chemistry, Bijvoet Center for Biomolecular Research, Faculty of Science, Utrecht University, Utrecht, Netherlands.
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$a von Heijne, Gunnar $u Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden. Science for Life Laboratory, Stockholm University, Solna, Sweden.
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$a Sanders, Rogier W $u Department of Medical Microbiology, Laboratory of Experimental Virology, Center for Infection and Immunity Amsterdam, Academic Medical Center, Amsterdam, Netherlands.
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$a Braakman, Ineke $u Cellular Protein Chemistry, Bijvoet Center for Biomolecular Research, Faculty of Science, Utrecht University, Utrecht, Netherlands.
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