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MBC in Press, published online ahead of print January 16, 2008
Mol. Biol. Cell 10.1091/mbc.E07-09-0861

A more recent version of this article appeared on March 1, 2008
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Submitted on September 5, 2007
Revised on December 26, 2007
Accepted on January 4, 2008

A Pachygyria-causing {alpha}-Tubulin Mutation Results in Inefficient Cycling with CCT and a Deficient Interaction with TBCB

Guoling Tian,* Xiang-Peng Kong,* Xavier H. Jaglin,{dagger} Jamel Chelly,{dagger} David Keays,{ddagger} and Nicholas J. Cowan*

*Department of Biochemistry, New York University Medical Center, New York, NY 10016; {dagger}Institut Cochin, Université René Descartes, Paris, F-75014, France; {ddagger}Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, United Kingdom

Monitoring Editor: Tim Stearns

The agyria (lissencephaly)/pachygyria phenotypes are catastrophic developmental diseases characterized by abnormal folds on the surface of the brain and disorganized cortical layering. In addition to mutations in at least four genes – LIS1, DCX, ARX and RELN– mutations in a human {alpha}-tubulin gene, TUBA1A, have recently been identified that cause these diseases. Here we show that one such mutation, R264C, leads to a diminished capacity of de novo tubulin heterodimer formation. We identify the mechanisms that contribute to this defect. First, there is a reduced efficiency whereby quasi-native {alpha}-tubulin folding intermediates are generated via ATP-dependent interaction with the cytosolic chaperonin, CCT. Second, there is a failure of CCT-generated folding intermediates to stably interact with TBCB, one of the five tubulin chaperones (TBCA-E) that participate in the pathway leading to the de novo assembly of the tubulin heterodimer. We describe the behavior of the R264C mutation in terms of its effect on the structural integrity of {alpha}-tubulin and its interaction with TBCB. In spite of its compromised folding efficiency, R264C molecules that do productively assemble into heterodimers are capable of copolymerizing into dynamic microtubules in vivo. The diminished production of TUBA1A tubulin in R264C individuals is consistent with haploinsufficiency as a cause of the disease phenotype.

Address correspondence to: Nicholas J. Cowan (cowann01{at}med.nyu.edu)






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