The SEC receptor recognizes a pentapeptide neodomain of α1-antitrypsin-protease complexes

Gregg Joslin, Robert Fallon, Joseph Bullock, Steven P. Adams, David H. Perlmutter

Research output: Contribution to journalArticle

89 Citations (Scopus)

Abstract

Formation of the covalently stabilized α-antitrypsin (α1-AT)-neutrophil elastase complex, the archetype of serpin-enzyme complexes, results in a structurally rearranged α1-AT molecule that possesses chemoattractant activities, mediates an increase in synthesis of α1-AT by mononuclear phagocytes and hepatocytes, and is more rapidly cleared from the circulation than is the native α1-AT molecule. We have recently identified an abundant, high affinity cell surface receptor on human hepatoma HepG2 cells and human monocytes that binds α1-AT-elastase complexes, mediates endocytosis and lysosomal degradation of α1-AT-elastase complexes, and induces an increase in synthesis of α1-AT. We have referred to this receptor as the serpin-enzyme complex, or SEC, receptor because it also recognizes complexes of serpins antithrombin III, α1-antichymotrypsin, and C1 inhibitor with their cognate enzymes. In the current study, we show that a pentapeptide domain in the carboxyl terminal fragment of α1-AT (amino acids 370-374, FVFLM) is sufficient for binding to the SEC receptor. A synthetic analog of this pentapeptide (peptide 105C, FVYLI) blocks binding and internalization of α1-AT-125I-trypsin complexes by HepG2 cells. 125I-Peptide 105C binds specifically and saturably to HepG2 cells, and its binding is blocked by α1-AT-trypsin or α1-AT-elastase complexes. Alterations of this sequence introduced into synthetic peptides (mutations, deletions, or scrambling) demonstrate that binding of the pentapeptide domain is sequence-specific. Comparisons with the sequences of other serpins in the corresponding region indicate that this pentapeptide neodomain is highly conserved.

Original languageEnglish (US)
Pages (from-to)11282-11288
Number of pages7
JournalJournal of Biological Chemistry
Volume266
Issue number17
StatePublished - 1991
Externally publishedYes

Fingerprint

Serpins
Pancreatic Elastase
Hep G2 Cells
Peptide Hydrolases
Trypsin
Peptides
Leukocyte Elastase
Molecules
Antithrombin III
Sequence Deletion
Chemotactic Factors
Cell Surface Receptors
Enzymes
Phagocytes
Endocytosis
Monocytes
Hepatocytes
Hepatocellular Carcinoma
Amino Acids
Degradation

ASJC Scopus subject areas

  • Biochemistry

Cite this

Joslin, G., Fallon, R., Bullock, J., Adams, S. P., & Perlmutter, D. H. (1991). The SEC receptor recognizes a pentapeptide neodomain of α1-antitrypsin-protease complexes. Journal of Biological Chemistry, 266(17), 11282-11288.

The SEC receptor recognizes a pentapeptide neodomain of α1-antitrypsin-protease complexes. / Joslin, Gregg; Fallon, Robert; Bullock, Joseph; Adams, Steven P.; Perlmutter, David H.

In: Journal of Biological Chemistry, Vol. 266, No. 17, 1991, p. 11282-11288.

Research output: Contribution to journalArticle

Joslin, G, Fallon, R, Bullock, J, Adams, SP & Perlmutter, DH 1991, 'The SEC receptor recognizes a pentapeptide neodomain of α1-antitrypsin-protease complexes', Journal of Biological Chemistry, vol. 266, no. 17, pp. 11282-11288.
Joslin G, Fallon R, Bullock J, Adams SP, Perlmutter DH. The SEC receptor recognizes a pentapeptide neodomain of α1-antitrypsin-protease complexes. Journal of Biological Chemistry. 1991;266(17):11282-11288.
Joslin, Gregg ; Fallon, Robert ; Bullock, Joseph ; Adams, Steven P. ; Perlmutter, David H. / The SEC receptor recognizes a pentapeptide neodomain of α1-antitrypsin-protease complexes. In: Journal of Biological Chemistry. 1991 ; Vol. 266, No. 17. pp. 11282-11288.
@article{1005855c97d54f72abc1acd75ddbf838,
title = "The SEC receptor recognizes a pentapeptide neodomain of α1-antitrypsin-protease complexes",
abstract = "Formation of the covalently stabilized α-antitrypsin (α1-AT)-neutrophil elastase complex, the archetype of serpin-enzyme complexes, results in a structurally rearranged α1-AT molecule that possesses chemoattractant activities, mediates an increase in synthesis of α1-AT by mononuclear phagocytes and hepatocytes, and is more rapidly cleared from the circulation than is the native α1-AT molecule. We have recently identified an abundant, high affinity cell surface receptor on human hepatoma HepG2 cells and human monocytes that binds α1-AT-elastase complexes, mediates endocytosis and lysosomal degradation of α1-AT-elastase complexes, and induces an increase in synthesis of α1-AT. We have referred to this receptor as the serpin-enzyme complex, or SEC, receptor because it also recognizes complexes of serpins antithrombin III, α1-antichymotrypsin, and C1 inhibitor with their cognate enzymes. In the current study, we show that a pentapeptide domain in the carboxyl terminal fragment of α1-AT (amino acids 370-374, FVFLM) is sufficient for binding to the SEC receptor. A synthetic analog of this pentapeptide (peptide 105C, FVYLI) blocks binding and internalization of α1-AT-125I-trypsin complexes by HepG2 cells. 125I-Peptide 105C binds specifically and saturably to HepG2 cells, and its binding is blocked by α1-AT-trypsin or α1-AT-elastase complexes. Alterations of this sequence introduced into synthetic peptides (mutations, deletions, or scrambling) demonstrate that binding of the pentapeptide domain is sequence-specific. Comparisons with the sequences of other serpins in the corresponding region indicate that this pentapeptide neodomain is highly conserved.",
author = "Gregg Joslin and Robert Fallon and Joseph Bullock and Adams, {Steven P.} and Perlmutter, {David H.}",
year = "1991",
language = "English (US)",
volume = "266",
pages = "11282--11288",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "17",

}

TY - JOUR

T1 - The SEC receptor recognizes a pentapeptide neodomain of α1-antitrypsin-protease complexes

AU - Joslin, Gregg

AU - Fallon, Robert

AU - Bullock, Joseph

AU - Adams, Steven P.

AU - Perlmutter, David H.

PY - 1991

Y1 - 1991

N2 - Formation of the covalently stabilized α-antitrypsin (α1-AT)-neutrophil elastase complex, the archetype of serpin-enzyme complexes, results in a structurally rearranged α1-AT molecule that possesses chemoattractant activities, mediates an increase in synthesis of α1-AT by mononuclear phagocytes and hepatocytes, and is more rapidly cleared from the circulation than is the native α1-AT molecule. We have recently identified an abundant, high affinity cell surface receptor on human hepatoma HepG2 cells and human monocytes that binds α1-AT-elastase complexes, mediates endocytosis and lysosomal degradation of α1-AT-elastase complexes, and induces an increase in synthesis of α1-AT. We have referred to this receptor as the serpin-enzyme complex, or SEC, receptor because it also recognizes complexes of serpins antithrombin III, α1-antichymotrypsin, and C1 inhibitor with their cognate enzymes. In the current study, we show that a pentapeptide domain in the carboxyl terminal fragment of α1-AT (amino acids 370-374, FVFLM) is sufficient for binding to the SEC receptor. A synthetic analog of this pentapeptide (peptide 105C, FVYLI) blocks binding and internalization of α1-AT-125I-trypsin complexes by HepG2 cells. 125I-Peptide 105C binds specifically and saturably to HepG2 cells, and its binding is blocked by α1-AT-trypsin or α1-AT-elastase complexes. Alterations of this sequence introduced into synthetic peptides (mutations, deletions, or scrambling) demonstrate that binding of the pentapeptide domain is sequence-specific. Comparisons with the sequences of other serpins in the corresponding region indicate that this pentapeptide neodomain is highly conserved.

AB - Formation of the covalently stabilized α-antitrypsin (α1-AT)-neutrophil elastase complex, the archetype of serpin-enzyme complexes, results in a structurally rearranged α1-AT molecule that possesses chemoattractant activities, mediates an increase in synthesis of α1-AT by mononuclear phagocytes and hepatocytes, and is more rapidly cleared from the circulation than is the native α1-AT molecule. We have recently identified an abundant, high affinity cell surface receptor on human hepatoma HepG2 cells and human monocytes that binds α1-AT-elastase complexes, mediates endocytosis and lysosomal degradation of α1-AT-elastase complexes, and induces an increase in synthesis of α1-AT. We have referred to this receptor as the serpin-enzyme complex, or SEC, receptor because it also recognizes complexes of serpins antithrombin III, α1-antichymotrypsin, and C1 inhibitor with their cognate enzymes. In the current study, we show that a pentapeptide domain in the carboxyl terminal fragment of α1-AT (amino acids 370-374, FVFLM) is sufficient for binding to the SEC receptor. A synthetic analog of this pentapeptide (peptide 105C, FVYLI) blocks binding and internalization of α1-AT-125I-trypsin complexes by HepG2 cells. 125I-Peptide 105C binds specifically and saturably to HepG2 cells, and its binding is blocked by α1-AT-trypsin or α1-AT-elastase complexes. Alterations of this sequence introduced into synthetic peptides (mutations, deletions, or scrambling) demonstrate that binding of the pentapeptide domain is sequence-specific. Comparisons with the sequences of other serpins in the corresponding region indicate that this pentapeptide neodomain is highly conserved.

UR - http://www.scopus.com/inward/record.url?scp=0025822649&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0025822649&partnerID=8YFLogxK

M3 - Article

VL - 266

SP - 11282

EP - 11288

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 17

ER -