Evidence for furin-type activity-mediated C-terminal processing of profibrillin-1 and interference in the processing by certain mutations

L. Lönnqvist, D. Reinhardt, L. Sakai, L. Peltonen

Research output: Contribution to journalArticle

48 Scopus citations

Abstract

Fibrillin-1 is a major component of the 10 nm microfibrils of the extracellular matrix (ECM). It is synthesized as an ~350 kDa precursor molecule, profibrillin-1, which is proteolytically processed into its biologically active ~320 kDa form. Furin, a calcium-dependent endoprotease of the subtilisin family, which is known to be the processing enzyme for a variety of proproteins, is believed to be responsible for the N-terminal proteolytic cleavage of profibrillin-1. In this article we provide several lines of evidence that the C-terminal trimming of profibrillin-1 also occurs via a furin-type activity. Edman degradation of a small recombinant C-terminal subdomain of fibrillin-1 revealed complete processing of the peptide immediately after the tribasic recognition sequence (R-X-K/R-R) for furin. In vitro expression experiments using another recombinant construct consisting of the C-terminal half of fibrillin-1 indicated that disruption of the putative recognition sequence for furin by site-directed mutagenesis drastically impairs proteolytic processing of the propeptide. In addition, our results suggest that the N-terminal half of fibrillin-1 is necessary for its incorporation into the ECM.

Original languageEnglish (US)
Pages (from-to)2039-2044
Number of pages6
JournalHuman molecular genetics
Volume7
Issue number13
StatePublished - Dec 1 1998

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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