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J. Biol. Chem., Vol. 278, Issue 12, 10381-10388, March 21, 2003
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From the The transmembrane and multidomain neural adhesion
molecule L1 plays important functional roles in the developing and
adult nervous system. L1 is proteolytically processed at two distinct sites within the extracellular domain, leading to the generation of
different fragments. In this report, we present evidence that the
proprotein convertase PC5A is the protease that cleaves L1 in the third
fibronectin type III domain, whereas the proprotein convertases furin,
PC1, PC2, PACE4, and PC7 are not effective in cleaving L1. Analysis of
mutations revealed Arg845 to be the site of cleavage
generating the N-terminal 140-kDa fragment. This fragment was present
in the hippocampus, which expresses PC5A, but was not detectable in the
cerebellum, which does not express PC5A. The 140-kDa L1 fragment was
found to be tightly associated with the full-length 200-kDa L1
molecule. The complex dissociated from the membrane upon cleavage by a
protease acting at a more membrane-proximal site of full-length L1.
This proteolytic cleavage was inhibited by the metalloprotease
inhibitor GM 6001 and enhanced by a calmodulin inhibitor.
L1-dependent neurite outgrowth of cerebellar neurons was
inhibited by GM 6001, suggesting that proteolytic processing of L1 by a
metalloprotease is involved in neurite outgrowth.
The Proprotein Convertase PC5A and a Metalloprotease Are
Involved in the Proteolytic Processing of the Neural Adhesion
Molecule L1*
,,, and¶
Zentrum für Molekulare Neurobiologie,
University of Hamburg, Martinistrasse 52, D-20246 Hamburg,
Germany and the § Laboratory of Biochemical
Neuroendocrinology Clinical Research Institute of Montreal,
110 Pine Avenue West, Montreal, Quebec H2W1R7, Canada
*
This work was supported by German Research Society Grant
Kl1378/1-1 (to R. K. and M. S.) and by Canadian Institutes of Health Research Group Grant MGC-11474 and a Protein Engineering Network of Centres of Excellence grant (to N. G. S.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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