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Originally published as Genetics Published Articles Ahead of Print on October 11, 2005.

Genetics, Vol. 172, 355-362, January 2006, Copyright © 2006
doi:10.1534/genetics.105.051979

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Drosophila Target of Rapamycin Kinase Functions as a Multimer

Yong Zhang*, Charles J. Billington, Jr.{dagger}, Duojia Pan* and Thomas P. Neufeld{dagger},1

* Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2185 and {dagger} Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota 55455

1 Corresponding author: Department of Genetics, Cell Biology and Development, University of Minnesota, 6-160 Jackson Hall, 321 Church St. S.E., Minneapolis, MN 55455.
E-mail: neufeld{at}med.umn.edu

Target of rapamycin (TOR) is a conserved regulator of cell growth and metabolism that integrates energy, growth factor, and nutrient signals. The 280-kDa TOR protein functions as the catalytic component of two large multiprotein complexes and consists of an N-terminal HEAT-repeat domain and a C-terminal Ser/Thr kinase domain. Here we describe an allelic series of mutations in the Drosophila Tor gene and show that combinations of mutations in the HEAT and kinase domains of TOR display the rare genetic phenomenon of intragenic complementation, in which two or more defective proteins assemble to form a functional multimer. We present biochemical evidence that TOR self-associates in vivo and show that this multimerization is unaffected by positive or negative signals upstream of TOR. Consistent with multimerization of TOR, recessive mutations in the HEAT and kinase domains can dominantly interfere with wild-type TOR function in cells lacking TSC1 or TSC2. TOR multimerization thus partially accounts for the high apparent molecular weight of TOR complexes and offers novel therapeutic strategies for pathologies stemming from TOR hyperactivity.




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