Nardilysin (N-arginine dibasic convertase, or NRDc) is a cytosolic and cell-surface metalloendopeptidase that, in vitro, cleaves substrates upstream of Arg or Lys in basic pairs. NRDc differs from most of the other members of the M16 family of metalloendopeptidases by a 90 amino acid acidic domain (DAC) inserted close to its active site. At the cell surface, NRDc binds heparin-binding epidermal growth factor-like growth factor (HB-EGF) and enhances HB-EGF-induced cell migration. An active-site mutant of NRDc fulfills this function as well as wild-type NRDc, indicating that the enzyme activity is not required for this process. We now demonstrate that NRDc starts at Met49. Furthermore, we show that HB-EGF not only binds to NRDc but also potently inhibits its enzymic activity. NRDc—HB-EGF interaction involves the 21 amino acid heparin-binding domain (P21) of the growth factor, the DAC of NRDc and most probably its active site. Only disulphide-bonded P21 dimers are inhibitory. We also show that Ca2+, via the DAC, regulates both NRDc activity and HB-EGF binding. We conclude that the DAC is thus a key regulatory element for the two distinct functions that NRDc fulfills, i.e. as an HB-EGF modulator and a peptidase.
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October 2002
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Research Article|
October 01 2002
The metalloendopeptidase nardilysin (NRDc) is potently inhibited by heparin-binding epidermal growth factor-like growth factor (HB-EGF) Available to Purchase
Véronique HOSPITAL;
Véronique HOSPITAL
1
∗Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, Montreal, Quebec H2W 1R7, Canada
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Eiichiro NISHI;
Eiichiro NISHI
†Departments of Surgical Research and Pathology, Children's Hospital and Harvard Medical School, Boston, MA 02115, U.S.A.,
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Michael KLAGSBRUN;
Michael KLAGSBRUN
†Departments of Surgical Research and Pathology, Children's Hospital and Harvard Medical School, Boston, MA 02115, U.S.A.,
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Paul COHEN;
Paul COHEN
‡Laboratoire de Biochimie des Signaux Régulateurs Cellulaires et Moléculaires, UMR 7631 CNRS, Université Pierre et Marie Curie, 96 Bd Raspail, 75006 Paris, France
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Nabil G. SEIDAH;
Nabil G. SEIDAH
∗Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, Montreal, Quebec H2W 1R7, Canada
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Annik PRAT
Annik PRAT
2
∗Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, Montreal, Quebec H2W 1R7, Canada
2To whom correspondence should be addressed (e-mail [email protected]).
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Publisher: Portland Press Ltd
Received:
May 23 2002
Revision Received:
June 27 2002
Accepted:
July 03 2002
Accepted Manuscript online:
July 03 2002
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2002
2002
Biochem J (2002) 367 (1): 229–238.
Article history
Received:
May 23 2002
Revision Received:
June 27 2002
Accepted:
July 03 2002
Accepted Manuscript online:
July 03 2002
Citation
Véronique HOSPITAL, Eiichiro NISHI, Michael KLAGSBRUN, Paul COHEN, Nabil G. SEIDAH, Annik PRAT; The metalloendopeptidase nardilysin (NRDc) is potently inhibited by heparin-binding epidermal growth factor-like growth factor (HB-EGF). Biochem J 1 October 2002; 367 (1): 229–238. doi: https://doi.org/10.1042/bj20020822
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