The goal of this research is to understand the molecular mechanism of microtubule (MT) polymerization and depolymerization which are mediated by conserved families of proteins. These proteins act as tubulin polymerases and depolymerases at MT plus ends. Under the mentorship of Dr. Stephen C. Harrison at Harvard Medical School, I have developed a molecular model using electron microscopy and biochemistry for how budding yeast Stu2 dimers and Xenopus XMAP215 monomers bind tubulin dimer via their conseved N-terminal TOG domains. I have determined the structure of a TOG domain using x-ray crystallography and show a narrow conserved surface on the TOG paddle-like structure is the tubulin binding interface. My work suggests a hypothesis for how TOG domains enhance tubulin polymerization at MT plus ends. We are currently studying the structure of TOG domains bound to tubulin dimer. In the mentored phase, I will determine the structure of TOG domains-tubulin dimer complex to understand how TOG domains bind and enhance tubulin assembly. I also intend to explore the role of different TOG domains in enhancing MT assembly using microscopy methodologies in collaberation with the laboratories of Anthony A Hyman and Jonathan Howard at the Max Planck institute in Germany. ? In the independent phase, I aim to understand how two classes of conserved kinesin superfamily proteins (kinesins-13 and 8) mediate the disassembly of MTs, acting as MT depoymerases. A hypothesis has been developed about how the motor domains may force tubulin at MT ends to curve leading to MT disassembly. I intend to determine structures for their motor domain in action, while bound to tubulin dimer to understand the mechanism of MT depolymerization. I also intend to determine the role of conservd features in their depolymerase activity. I will then explore the antagonism and interaction between MT polymerase and depolymerases in interphase and its regulation upon the onset of mitotic cell division. This antagonism leads to slow MT dynamics in interphase and fast MT dynamics in mitosis. A direct role of phosphorylation by mitotic kinases will be explored during the transition between interphase and mitosis.? Defects in the regulation of cell division are directly linked to human genetic defects and cancers. The results from this study will broaden our understanding of this regulation and provide new targets for cancer therapy. ?

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Career Transition Award (K99)
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Special Emphasis Panel (ZGM1-BRT-9 (KR))
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Deatherage, James F
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Harvard University
Schools of Medicine
United States
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Al-Bassam, Jawdat; Chang, Fred (2011) Regulation of microtubule dynamics by TOG-domain proteins XMAP215/Dis1 and CLASP. Trends Cell Biol 21:604-14
Cho, U-S; Corbett, K D; Al-Bassam, J et al. (2010) Molecular structures and interactions in the yeast kinetochore. Cold Spring Harb Symp Quant Biol 75:395-401
Al-Bassam, Jawdat; Kim, Hwajin; Brouhard, Gary et al. (2010) CLASP promotes microtubule rescue by recruiting tubulin dimers to the microtubule. Dev Cell 19:245-58