Regulation of dynamic microtubules (MTs) is critical for cellular processes such as cell division, cell migration, cell polarity, organelle movements and nuclear positioning. Understanding conserved mechanisms of MT regulation are highly relevant to human biology and diseases such as cancer, neuronal diseases and wound healing. In this grant, we aim to elucidate fundamental conserved mechanisms responsible for MT regulation by studying MT plus end tracking proteins (+TIPs). These proteins coat the MT plus end and control the assembly, stability and disassembly of these polymers. In general, how these proteins work collectively to regulate MT dynamics in vivo is a pressing question in this active field. We study MT regulation using in vivo and in vitro approaches, using the fission yeast Schizosaccharomyces pombe as a tractable, simple model system. The XMAP215/Alp14 family of +TIPs is emerging as one of the most important of the +TIPs. These tubulin-binding proteins function as MT polymerases that add tubulin onto the ends of growing MT. Our preliminary results suggest that it has additional functions in MT nucleation and disassembly.
Our specific aims are: 1) To define how Alp14 works with gamma tubulin complex for MT nucleation; 2) To determine how Alp14 and the kinesin-8 Klp5/6 regulate the disassembly of MTs; 3) To elucidate the molecular mechanisms of how XMAP215/Alp14 proteins interact with tubulin to regulate MT dynamics.
Microtubules are hollow protein tubes within cells that grow and shrink to move cellular components, shape the cell, and bring about cell division. In this grant, we study a key protein that binds to the very end of the microtubule in order to regulate the growth and shrinkage of these tubes. These studies will have broad relevance to human diseases such as cancer, stem cells and neurological diseases.
|Nithianantham, Stanley; Cook, Brian D; Beans, Madeleine et al. (2018) Structural basis of tubulin recruitment and assembly by microtubule polymerases with tumor overexpressed gene (TOG) domain arrays. Elife 7:|