TY - JOUR
T1 - Evidence for furin-type activity-mediated C-terminal processing of profibrillin-1 and interference in the processing by certain mutations
AU - Lönnqvist, L.
AU - Reinhardt, D.
AU - Sakai, L.
AU - Peltonen, L.
N1 - Funding Information:
The financial support of the Maud Kuistila Foundation and Shriners Hospital is gratefully acknowledged.
PY - 1998/12
Y1 - 1998/12
N2 - 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.
AB - 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.
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U2 - 10.1093/hmg/7.13.2039
DO - 10.1093/hmg/7.13.2039
M3 - Article
C2 - 9817919
AN - SCOPUS:0031789366
SN - 0964-6906
VL - 7
SP - 2039
EP - 2044
JO - Human molecular genetics
JF - Human molecular genetics
IS - 13
ER -