Asparagine-proline sequence within membrane-spanning segment of SREBP triggers intramembrane Site-2 protease

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103 Citations (Scopus)

Abstract

The NH2-terminal domains of membrane-bound sterol regulatory element- binding proteins (SREBPs) are released into the cytosol by regulated intramembrane proteolysis, after which they enter the nucleus to activate genes encoding lipid biosynthetic enzymes. Intramembrane proteolysis is catalyzed by Site-2 protease (S2P), a hydrophobic zinc metalloprotease that cleaves SREBPs at a membrane-embedded leucine-cysteine bond. In the current study, we use domain-swapping methods to localize the residues within the SREBP-2 membrane-spanning segment that are required for cleavage by S2P. The studies reveal a requirement for an asparagine-proline sequence in the middle third of the transmembrane segment. We propose a model in which the asparagine-proline sequence serves as an NH2-terminal cap for a portion of the transmembrane α-helix of SREBP, allowing the remainder of the α-helix to unwind partially to expose the peptide bond for cleavage by S2P.

Original languageEnglish (US)
Pages (from-to)5123-5128
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume97
Issue number10
DOIs
StatePublished - May 9 2000

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Sterol Regulatory Element Binding Proteins
Asparagine
Proline
Peptide Hydrolases
Proteolysis
Membranes
Sterol Regulatory Element Binding Protein 2
Metalloproteases
Leucine
Cytosol
Cysteine
Zinc
Lipids
Peptides
Enzymes
Genes

Keywords

  • Cholesterol metabolism
  • Membrane proteins
  • Proteolysis

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

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title = "Asparagine-proline sequence within membrane-spanning segment of SREBP triggers intramembrane Site-2 protease",
abstract = "The NH2-terminal domains of membrane-bound sterol regulatory element- binding proteins (SREBPs) are released into the cytosol by regulated intramembrane proteolysis, after which they enter the nucleus to activate genes encoding lipid biosynthetic enzymes. Intramembrane proteolysis is catalyzed by Site-2 protease (S2P), a hydrophobic zinc metalloprotease that cleaves SREBPs at a membrane-embedded leucine-cysteine bond. In the current study, we use domain-swapping methods to localize the residues within the SREBP-2 membrane-spanning segment that are required for cleavage by S2P. The studies reveal a requirement for an asparagine-proline sequence in the middle third of the transmembrane segment. We propose a model in which the asparagine-proline sequence serves as an NH2-terminal cap for a portion of the transmembrane α-helix of SREBP, allowing the remainder of the α-helix to unwind partially to expose the peptide bond for cleavage by S2P.",
keywords = "Cholesterol metabolism, Membrane proteins, Proteolysis",
author = "Jin Ye and Dav{\'e}, {Utpal P.} and Grishin, {Nick V.} and Goldstein, {Joseph L.} and Brown, {Michael S.}",
year = "2000",
month = "5",
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doi = "10.1073/pnas.97.10.5123",
language = "English (US)",
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pages = "5123--5128",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
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T1 - Asparagine-proline sequence within membrane-spanning segment of SREBP triggers intramembrane Site-2 protease

AU - Ye, Jin

AU - Davé, Utpal P.

AU - Grishin, Nick V.

AU - Goldstein, Joseph L.

AU - Brown, Michael S.

PY - 2000/5/9

Y1 - 2000/5/9

N2 - The NH2-terminal domains of membrane-bound sterol regulatory element- binding proteins (SREBPs) are released into the cytosol by regulated intramembrane proteolysis, after which they enter the nucleus to activate genes encoding lipid biosynthetic enzymes. Intramembrane proteolysis is catalyzed by Site-2 protease (S2P), a hydrophobic zinc metalloprotease that cleaves SREBPs at a membrane-embedded leucine-cysteine bond. In the current study, we use domain-swapping methods to localize the residues within the SREBP-2 membrane-spanning segment that are required for cleavage by S2P. The studies reveal a requirement for an asparagine-proline sequence in the middle third of the transmembrane segment. We propose a model in which the asparagine-proline sequence serves as an NH2-terminal cap for a portion of the transmembrane α-helix of SREBP, allowing the remainder of the α-helix to unwind partially to expose the peptide bond for cleavage by S2P.

AB - The NH2-terminal domains of membrane-bound sterol regulatory element- binding proteins (SREBPs) are released into the cytosol by regulated intramembrane proteolysis, after which they enter the nucleus to activate genes encoding lipid biosynthetic enzymes. Intramembrane proteolysis is catalyzed by Site-2 protease (S2P), a hydrophobic zinc metalloprotease that cleaves SREBPs at a membrane-embedded leucine-cysteine bond. In the current study, we use domain-swapping methods to localize the residues within the SREBP-2 membrane-spanning segment that are required for cleavage by S2P. The studies reveal a requirement for an asparagine-proline sequence in the middle third of the transmembrane segment. We propose a model in which the asparagine-proline sequence serves as an NH2-terminal cap for a portion of the transmembrane α-helix of SREBP, allowing the remainder of the α-helix to unwind partially to expose the peptide bond for cleavage by S2P.

KW - Cholesterol metabolism

KW - Membrane proteins

KW - Proteolysis

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U2 - 10.1073/pnas.97.10.5123

DO - 10.1073/pnas.97.10.5123

M3 - Article

VL - 97

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JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

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