Cofactor A Is a Molecular Chaperone Required for β-Tubulin Folding: Functional and Structural Characterization

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Abstract
Actin and tubulin polypeptide chains acquire their native conformation in the presence of the chaperonin containing TCP-1 (CCT) and, in the case of α- and β-tubulin additional protein cofactors. We recently identified one of these cofactors, termed cofactor A, that is required for the proper folding of the β-tubulin chain [Gao et al. (1994) J. Cell. Biol. 125, 989−996]. We show here that cofactor A, a monomeric protein that has no measurable affinity for nucleotides, is a highly conserved protein among vertebrates. Its NH2-terminal region is essential for the structural integrity of the protein and consequently for its activity. We demonstrate that cofactor A does not interact with CCT nor does it affect the intrinsic ATPase activity of CCT, alone or in the presence of different target proteins. Thus, unlike GroES, cofactor A does not modulate or coordinate ATP hydrolysis. It does not act as a nucleotide exchange factor or a catalyst in tubulin folding. Rather, we demonstrate that cofactor A participates in the tubulin folding process by interacting with a folding intermediate of β-tubulin that is released from CCT. Our data imply that cofactor A is a chaperone involved in tubulin folding.

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