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J. Biol. Chem., Vol. 276, Issue 29, 26792-26798, July 20, 2001
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From the Department of Medicine, Palo Alto VA Medical Center and
Stanford University, Palo Alto, California 94304
Type I keratins K18 and K19 undergo
caspase-mediated degradation during apoptosis. Two known K18 caspase
cleavage sites are aspartates in the consensus sequences VEVDA and
DALDS, located within the rod domain and tail domain, respectively.
Several K14 (another type I keratin) mutations within the caspase
cleavage motif have been described in patients with epidermolysis
bullosa simplex. Here we use extensive mutational analysis to show that K19 and K14 are caspase substrates and that the ability to undergo caspase-mediated digestion of K18, K19, or K14 is highly dependent on
the location and nature of the mutation within the caspase cleavage
motif. Caspase cleavage of K14 occurs at the aspartate of VEMDA, a
consensus sequence found in type I keratins K12-17 with similar but
not identical sequences in K18 and K19. For K18, apoptosis-induced
cleavage occurs sequentially, first at 393DALD and
then at 234VEVD. Hyperphosphorylation of K18 protects from
caspase-3 in vitro digestion at 234VEVD but not
at 393DALD. Hence, keratins K12-17 are likely caspase
substrates during apoptosis. Keratin hyperphosphorylation, which occurs
early in apoptosis, protects from caspase-mediated K18 digestion in a
cleavage site-specific manner. Mutations in epidermolysis bullosa
simplex patients could interfere with K14 degradation during
apoptosis, depending on their location.
Effect of Mutation and Phosphorylation of Type I Keratins on Their
Caspase-mediated Degradation*
*
This work was supported by National Institutes of
Health Grant DK47918 and VA Career Development Awards (to M. B. O.).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.
To whom correspondence should be addressed: Palo Alto VA Medical
Center, Mail Code 154J, 3801 Miranda Ave., Palo Alto, CA 94304. Fax:
415-852-3259.
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