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Mol Biol Cell. 2014 Aug 15;25(16):2375-92. doi: 10.1091/mbc.E13-08-0501. Epub 2014 Jun 25.

The XMAP215 family drives microtubule polymerization using a structurally diverse TOG array.

Author information

1
Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599Graduate Program in Molecular and Cellular Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
2
Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
3
Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599Carolina Center for Genome Science, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
4
Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 kslep@bio.unc.edu.

Abstract

XMAP215 family members are potent microtubule (MT) polymerases, with mutants displaying reduced MT growth rates and aberrant spindle morphologies. XMAP215 proteins contain arrayed tumor overexpressed gene (TOG) domains that bind tubulin. Whether these TOG domains are architecturally equivalent is unknown. Here we present crystal structures of TOG4 from Drosophila Msps and human ch-TOG. These TOG4 structures architecturally depart from the structures of TOG domains 1 and 2, revealing a conserved domain bend that predicts a novel engagement with α-tubulin. In vitro assays show differential tubulin-binding affinities across the TOG array, as well as differential effects on MT polymerization. We used Drosophila S2 cells depleted of endogenous Msps to assess the importance of individual TOG domains. Whereas a TOG1-4 array largely rescues MT polymerization rates, mutating tubulin-binding determinants in any single TOG domain dramatically reduces rescue activity. Our work highlights the structurally diverse yet positionally conserved TOG array that drives MT polymerization.

PMID:
24966168
PMCID:
PMC4142611
DOI:
10.1091/mbc.E13-08-0501
[Indexed for MEDLINE]
Free PMC Article

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