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Vol. 10, Issue 1, 105-118, January 1999
and
*Department of Biological Sciences, Lehigh University, Bethlehem,
Pennsylvania 18015; and
Oncoprotein 18/stathmin (Op18) has been identified recently
as a protein that destabilizes microtubules, but the mechanism of
destabilization is currently controversial. Based on in vitro microtubule assembly assays, evidence has been presented supporting conflicting destabilization models of either tubulin sequestration or
promotion of microtubule catastrophes. We found that Op18 can destabilize microtubules by both of these mechanisms and that these
activities can be dissociated by changing pH. At pH 6.8, Op18 slowed
microtubule elongation and increased catastrophes at both plus and
minus ends, consistent with a tubulin-sequestering activity. In
contrast, at pH 7.5, Op18 promoted microtubule catastrophes, particularly at plus ends, with little effect on elongation rates at
either microtubule end. Dissociation of tubulin-sequestering and
catastrophe-promoting activities of Op18 was further demonstrated by
analysis of truncated Op18 derivatives. Lack of a C-terminal region of
Op18 (aa 100-147) resulted in a truncated protein that lost
sequestering activity at pH 6.8 but retained catastrophe-promoting activity. In contrast, lack of an N-terminal region of Op18 (aa 5-25)
resulted in a truncated protein that still sequestered tubulin at pH
6.8 but was unable to promote catastrophes at pH 7.5. At pH 6.8, both
the full length and the N-terminal-truncated Op18 bound tubulin,
whereas truncation at the C-terminus resulted in a pronounced decrease
in tubulin binding. Based on these results, and a previous study
documenting a pH-dependent change in binding affinity between Op18 and
tubulin, it is likely that tubulin sequestering observed at lower pH
resulted from the relatively tight interaction between Op18 and tubulin
and that this tight binding requires the C-terminus of Op18; however,
under conditions in which Op18 binds weakly to tubulin (pH 7.5), Op18
stimulated catastrophes without altering tubulin subunit association or
dissociation rates, and Op18 did not depolymerize microtubules capped
with guanylyl (Department for Cell and
Molecular Biology, University of Umeå, Umeå S-901 87, Sweden
, 
)-methylene diphosphonate-tubulin
subunits. We hypothesize that weak binding between Op18 and tubulin
results in free Op18, which is available to interact with microtubule
ends and thereby promote catastrophes by a mechanism that likely
involves GTP hydrolysis.
Present address: Department of Biology,
University of North Carolina, Chapel Hill, NC 27599-3280.
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