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Research Article

Mechanism for the catastrophe-promoting activity of the microtubule destabilizer Op18/stathmin

Kamlesh K. Gupta, Chunlei Li, Aranda Duan, Emily O. Alberico, Oleg V. Kim, Mark S. Alber, and Holly V. Goodson
  1. aDepartment of Chemistry and Biochemistry,
  2. bDepartment of Applied and Computational Mathematics and Statistics,
  3. cInterdisciplinary Center for the Study of Biocomplexity, and
  4. eDepartment of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556; and
  5. dDepartment of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202

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PNAS December 17, 2013 110 (51) 20449-20454; https://doi.org/10.1073/pnas.1309958110
Kamlesh K. Gupta
aDepartment of Chemistry and Biochemistry,
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  • For correspondence: kgupta1@nd.edu hgoodson@nd.edu
Chunlei Li
bDepartment of Applied and Computational Mathematics and Statistics,
cInterdisciplinary Center for the Study of Biocomplexity, and
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Aranda Duan
aDepartment of Chemistry and Biochemistry,
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Emily O. Alberico
aDepartment of Chemistry and Biochemistry,
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Oleg V. Kim
bDepartment of Applied and Computational Mathematics and Statistics,
cInterdisciplinary Center for the Study of Biocomplexity, and
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Mark S. Alber
bDepartment of Applied and Computational Mathematics and Statistics,
cInterdisciplinary Center for the Study of Biocomplexity, and
dDepartment of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202
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Holly V. Goodson
aDepartment of Chemistry and Biochemistry,
cInterdisciplinary Center for the Study of Biocomplexity, and
eDepartment of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556; and
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  • For correspondence: kgupta1@nd.edu hgoodson@nd.edu
  1. Edited by Ronald D. Vale, Howard Hughes Medical Institute and University of California, San Francisco, CA, and approved October 23, 2013 (received for review June 3, 2013)

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Significance

The microtubule (MT) cytoskeleton is a dynamic polymer network that plays a crucial role in cell function and disease. MT assembly and dynamics are precisely controlled; a key regulator is the MT destabilizer known as stathmin. Stathmin’s mechanism of action remains controversial: one well-supported model is that it reduces polymer indirectly by sequestering MT subunits; the alternative is that it acts directly on MTs by an as yet unknown mechanism. We provide a resolution to this debate by presenting experimental evidence that stathmin can act directly on MTs and does so by binding and destabilizing exposed protofilaments. Computer simulations performed in parallel suggest that both the direct and sequestering activities are likely to be significant in a cellular context.

Abstract

Regulation of microtubule dynamic instability is crucial for cellular processes, ranging from mitosis to membrane transport. Stathmin (also known as oncoprotein 18/Op18) is a prominent microtubule destabilizer that acts preferentially on microtubule minus ends. Stathmin has been studied intensively because of its association with multiple types of cancer, but its mechanism of action remains controversial. Two models have been proposed. One model is that stathmin promotes microtubule catastrophe indirectly, and does so by sequestering tubulin; the other holds that stathmin alters microtubule dynamics by directly destabilizing growing microtubules. Stathmin’s sequestration activity is well established, but the mechanism of any direct action is mysterious because stathmin binds to microtubules very weakly. To address these issues, we have studied interactions between stathmin and varied tubulin polymers. We show that stathmin binds tightly to Dolastatin-10 tubulin rings, which mimic curved tubulin protofilaments, and that stathmin depolymerizes stabilized protofilament-rich polymers. These observations lead us to propose that stathmin promotes catastrophe by binding to and acting upon protofilaments exposed at the tips of growing microtubules. Moreover, we suggest that stathmin's minus-end preference results from interactions between stathmin's N terminus and the surface of α-tubulin that is exposed only at the minus end. Using computational modeling of microtubule dynamics, we show that these mechanisms could account for stathmin's observed activities in vitro, but that both the direct and sequestering activities are likely to be relevant in a cellular context. Taken together, our results suggest that stathmin can promote catastrophe by direct action on protofilament structure and interactions.

  • Zn-sheets
  • GMPCPP
  • T2S complex
  • computer simulation

Footnotes

  • ↵1To whom correspondence may be addressed. E-mail: kgupta1{at}nd.edu or hgoodson{at}nd.edu.
  • Author contributions: K.K.G. and H.V.G. designed research; K.K.G., C.L., A.D., E.O.A., and O.V.K. performed research; C.L., M.S.A., and H.V.G. contributed new computational tools; K.K.G., C.L., M.S.A., and H.V.G. analyzed data; and K.K.G., C.L., and H.V.G. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1309958110/-/DCSupplemental.

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Catastrophe-promoting mechanism of Op18/stathmin
Kamlesh K. Gupta, Chunlei Li, Aranda Duan, Emily O. Alberico, Oleg V. Kim, Mark S. Alber, Holly V. Goodson
Proceedings of the National Academy of Sciences Dec 2013, 110 (51) 20449-20454; DOI: 10.1073/pnas.1309958110

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Catastrophe-promoting mechanism of Op18/stathmin
Kamlesh K. Gupta, Chunlei Li, Aranda Duan, Emily O. Alberico, Oleg V. Kim, Mark S. Alber, Holly V. Goodson
Proceedings of the National Academy of Sciences Dec 2013, 110 (51) 20449-20454; DOI: 10.1073/pnas.1309958110
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