A novel class of fusion polypeptides inhibits exocytosis

Kenji Matsushita, Craig N. Morrell, Charles J. Lowenstein

Research output: Contribution to journalArticle

Abstract

N-Ethyl-maleimide-sensitive factor (NSF) plays a critical role in the regulation of exocytosis. NSF regulates exocytosis by interacting with a complex containing soluble NSF attachment protein receptor (SNARE) molecules, hydrolyzing ATP, and disassembling the SNARE complex. We hypothesized that peptide inhibitors of NSF would decrease exocytosis. We now report the development of a novel set of peptides that block exocytosis by inhibiting NSF activity. These NSF inhibitors are fusion polypeptides composed of an 11 amino acid human immunodeficiency virus transactivating regulatory protein (TAT) domain fused to a 22 amino acid NSF domain. These TAT-NSF fusion polypeptides cross endothelial cell membranes, inhibit NSF hydrolysis of ATP, decrease NSF disassembly of SNARE molecules, and block exocytosis of von Willebrand factor. Control peptides have no effect on exocytosis. TAT-NSF inhibitors administered to mice prolong the bleeding time. Blood concentrations of these TAT-NSF peptides rapidly decrease within 5 min after injection and then remain constant from 10 to 60 min after injection. These TAT-NSF compounds may be useful in the treatment of a variety of diseases in which exocytosis plays a prominent role, including myocardial infarction, stroke, thrombosis, and autoimmune disorders.

Original languageEnglish (US)
Pages (from-to)1137-1144
Number of pages8
JournalMolecular Pharmacology
Volume67
Issue number4
DOIs
StatePublished - Apr 2005

Fingerprint

Exocytosis
Peptides
Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins
SNARE Proteins
maleimide
Adenosine Triphosphate
Amino Acids
Injections
Bleeding Time
von Willebrand Factor
Thrombosis
Hydrolysis
Endothelial Cells
Stroke
Myocardial Infarction
Cell Membrane
HIV

ASJC Scopus subject areas

  • Pharmacology

Cite this

Matsushita, K., Morrell, C. N., & Lowenstein, C. J. (2005). A novel class of fusion polypeptides inhibits exocytosis. Molecular Pharmacology, 67(4), 1137-1144. https://doi.org/10.1124/mol.104.004275

A novel class of fusion polypeptides inhibits exocytosis. / Matsushita, Kenji; Morrell, Craig N.; Lowenstein, Charles J.

In: Molecular Pharmacology, Vol. 67, No. 4, 04.2005, p. 1137-1144.

Research output: Contribution to journalArticle

Matsushita, K, Morrell, CN & Lowenstein, CJ 2005, 'A novel class of fusion polypeptides inhibits exocytosis', Molecular Pharmacology, vol. 67, no. 4, pp. 1137-1144. https://doi.org/10.1124/mol.104.004275
Matsushita, Kenji ; Morrell, Craig N. ; Lowenstein, Charles J. / A novel class of fusion polypeptides inhibits exocytosis. In: Molecular Pharmacology. 2005 ; Vol. 67, No. 4. pp. 1137-1144.
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