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. Author manuscript; available in PMC: 2012 Jun 1.
Published in final edited form as: Curr Opin Genet Dev. 2011 Feb 1;21(3):286–294. doi: 10.1016/j.gde.2011.01.003

Figure 3. Summary depicting the proposed functional effects of disease-causing mutations in α–and β-tubulin.

Figure 3

(A) Overview of the tubulin heterodimer folding pathway. (A) (1) Nascent tubulin polypeptides are delivered to the cytosolic chaperone (CCT) in order to generate folding intermediates with GTP binding pockets. (2) α–and β-tubulin folding intermediates are then released, bound, and stabilized by a second set of chaperones, TBCA and TBCD (β-tubulin) and TBCB and TBCE (α–tubulin). (3) TBCD and TBCE form a complex to co-assemble the tubulin heterodimer, and bind TBCC. (4) This triggers the hydrolysis of GTP bound to β-tubulin and releases the tubulin heterodimer from the folding complex. (5) Following the exchange of GDP for GTP in β-tubulin, the heterodimers are capable of incorporating into microtubules. Mutations in tubulin are predicted to diminish the levels of functional tubulin heterodimers by disrupting the formation of the GTP binding pocket and/or interactions with protein chaperones. (B) Tubulin heterodimers assemble in a head to tail fashion to form a sheet of longitudinal protofilaments at the growing plus-end of a microtubule. Lateral interactions between adjacent protofilaments cause the open sheet to close and assemble into a hollow tube. (C) Mutations in α–and β-tubulin found at inter-heterodimer interfaces and/or regions of lateral protofilament interactions are predicted to impede the polymerization and dynamic properties of microtubules, resulting in microtubules that may be (1) relatively non-dynamic with reduced frequencies of growth and shortening, or (2) unstable and more likely to depolymerize. (D) The external microtubule surface interacts with kinesin and dynein motors, allowing the anterograde and retrograde transport of proteins and organelles along microtubules. MAPs also bind to the external surface and extrinsically regulate microtubule stability and dynamics. Mutations found in the external helices of tubulin are demonstrated or predicted to alter these types of protein interactions.