Protein folding is a critical step in the flow of information from genotype to phenotype. Misfolding underlies the pathogenesis of several diseases, particularly those involving neurodegeneration. We have discovered many of the chaperone proteins that facilitate the folding of tubulins, actins and other cytosolic proteins. These chaperones are prefoldin, the Type II chaperonin CCT, and five tubulin-specific chaperone proteins termed cofactors A-E. The cofactors a) function together as a tubulin dimer-making machine, and b) stimulate the GTPase activity of the native tubulin heterodimer, converting GTP-tubulin to GDP-tubulin. 1) We will test the hypothesis that the latter reaction regulates microtubule dynamics by neutralizing cofactor function in cultured cells and assaying the effect on the microtubule cytoskeleton. 2) We have shown that members of a family of small GTPases termed Aris (ADP-ribosylation factor-like proteins) interact with tubulin and/or tubulin-specific chaperones. We therefore propose to examine the regulation of cofactor and microtubute function by members of the Anl family. 3) We will investigate the function of two cofactor-related human proteins, RP2 and E-like, in vitro and in vitro. Mutations in the gene encoding RP2 cause retinitis pigmentosa; the function of E-like is unknown. 4) We will isolate and charactenize the McKusick-Kaufman Syndrome (MKKS) protein, which is pnedicted to be a new CCT-related Type II chaperonin, and study a) its presumptive ATPase and chaperone activities, and b) the range of target proteins to which it binds. 5) We will test the hypothesis that that the main function of CCT is to open up the nucleotidebinding pocket of certain newly synthesized proteins, so as to allow them to bind nucleotide.
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| Tian, Guoling; Huang, Melissa C; Parvari, Ruti et al. (2006) Cryptic out-of-frame translational initiation of TBCE rescues tubulin formation in compound heterozygous HRD. Proc Natl Acad Sci U S A 103:13491-6 |
| Wang, Yaqing; Tian, Guoling; Cowan, Nicholas J et al. (2006) Mutations affecting beta-tubulin folding and degradation. J Biol Chem 281:13628-35 |
