Worm Breeder's Gazette 15(1): 55 (October 1, 1997)

These abstracts should not be cited in bibliographies. Material contained herein should be treated as personal communication and should be cited as such only with the consent of the author.

The Growing Family of Kex2/subtilisin-like Proprotein Convertases in C. elegans

Colin Thacker, Ann M. Rose

Department of Medical Genetics, University of British Columbia, Vancouver, B.C. V6T 1Z3

        Many physiologically important proteins are expressed as large
inactive polypeptides, examples of which include growth factors,
growth factor receptors, hormones, peptide neurotransmitters, viral
glycoproteins and several metalloproteinases.  One way in which the
majority of these proproteins can be activated is by their limited
proteolytic cleavage at dibasic residues, a reaction catalyzed by
members of the kex2/subtilisin-like proprotein convertase family
(kexins or PC) of serine endoproteinases.  In vertebrates at least
seven different members of the family have been identified and
include furin, PC1/3, PC2, PC4, PC6, PC7 and PACE4.
        Our laboratory identified the first C. elegans member of the
family as bli-4 which encodes at least four gene products that arise
by alternative slicing.  The combined efforts of ourselves, the
genome sequencing consortium and the laboratory of Ian Dickerson at
the University of Miami School of Medicine, have identified a
further three nematode members of the family.  These three members
include genes with sequence similarity to furin and PC7, both of
which reside on the right arm of chromosome I, and a PC2 homologue
on chromosome V. We are interested in determining the role of each
of the kexins during C. elegans development and towards this end we
are attempting to isolate mutants for these three genes using the
targeted approach described by Gary Moulder and Bob Barstead at the
recent Worm meeting at Madison, WI (and personal communication).
        Continued studies on the bli-4 gene products suggests that the
major role of these convertases is the processing of cuticle
collagens during development, although we have not ruled out the
possibility that other substrates are cleaved.  We expect the furin
homologue like its vertebrate counterpart, to recognize a large
number of proproteins since this member of the PC family appears to
be the major role player.  Curiously the C. elegans gene differs
markedly at the carboxy-terminus when compared with that from
Drosophila and vertebrate proteins in that the worm protein does not
contain a transmembrane domain even though the protease domain is
highly conserved.  Vertebrate PC2 is active in the regulated
secretory pathway and has been shown to process a number of
prohormones and peptide neural transmitters.  PC7, like furin, is
expressed ubiquitously in mammalian cells and is thought to be
largely responsible, amongst other roles, for the processing of
viral glycoproproteins including infection by HIV.  Intriguingly,
the nematode gene F32A7.6 is expressed as part of an operon with
unc-54.  The kexin gene is trans-spliced to SL2 which is consistent
with it being the downstream gene in the operon.  Obviously,
expression of the kexin gene under the control of the unc-54
promoter raises the possibility that the role of the convertase is
highly restricted to muscle tissue and we have recently isolated
candidate mutants which may help us determine the function of this
serine endoproteinase.