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Department of Cell Biology and Anatomy, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
Many secreted bioactive signaling molecules,
including the yeast mating pheromones a-factor and
-factor, are initially synthesized as precursors requiring multiple intracellular processing enzymes to generate their mature forms. To identify new gene products involved in the biogenesis of a-factor in Saccharomyces cerevisiae, we carried out a screen for MATa-specific, mating-defective mutants. We have identified a new
mutant, ste24, in addition to previously known sterile
mutants. During its biogenesis in a wild-type strain, the
a-factor precursor undergoes a series of COOH-terminal CAAX modifications, two sequential NH2-terminal cleavage events, and export from the cell. Identification
of the a-factor biosynthetic intermediate that accumulates in the ste24 mutant revealed that STE24 is required for the first NH2-terminal proteolytic processing
event within the a-factor precursor, which takes place
after COOH-terminal CAAX modification is complete.
The STE24 gene product contains multiple predicted membrane spans, a zinc metalloprotease motif
(HEXXH), and a COOH-terminal ER retrieval signal
(KKXX). The HEXXH protease motif is critical for
STE24 activity, since STE24 fails to function when conserved residues within this motif are mutated. The identification of Ste24p homologues in a diverse group of
organisms, including Escherichia coli, Schizosaccharomyces pombe, Haemophilus influenzae, and Homo sapiens, indicates that Ste24p has been highly conserved
throughout evolution. Ste24p and the proteins related
to it define a new subfamily of proteins that are likely
to function as intracellular, membrane-associated zinc
metalloproteases.
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