Tetratricopeptide repeat (TPR) domains are made up of a repeated
alpha helical motif that folds into a characteristic binding groove.
The binding specificity of different TPR domains is dictated by the
different amino acid side chains projecting from their binding grooves.
Although the TPR motif is one of the most common structures found in the
human proteome, and though TPR proteins are unusually important for
viability in genetic studies of model organisms, this class of proteins
has been remarkably understudied. The expression of half of the 130 TPR
proteins encoded by the human genome remains hypothetical, and the
functions of most of the others remain poorly understood. Mutations in
TPR genes have, however, been implicated in diverse human genetic
diseases including Fanconi's anemia, Leber's congenital amaurosis,
Bardet-Biedl syndrome, peroxisome biogenesis disorders, chronic
granulomatous disease, and developmental dyslexia. The functions of the
proteins mutated in these diseases, however, remain largely
uncharacterized on a biochemical or cellular level.
Our studies have focused on a large subfamily of TPR proteins
that act as co-chaperones with hsp70 and hsp90 to regulate the folding
of steroid receptors. There is evidence that different co-chaperones
are important for the folding of different receptors, and that steroid
signaling can become impaired when the wrong TPR co-chaperones are
present. Projects are currently underway to determine which of these
co-chaperones is important for the activity of which receptors in living
cells. Since the hsp90 protein-folding pathway represents a target for
anti-neoplastic drugs, we are also attempting to develop specific
inhibitors of particular TPR-hsp90 interactions. Knowing that the main
function of TPR domains is to mediate protein-protein interactions, we
have recently begun to map the human TPR interactome. Identifying which
proteins bind to which TPR domains will allow us to dissect
previously-unrecognized signaling pathways, including some already known
to be involved in human disease. In pilot studies with twenty TPR
proteins, some previously uncharacterized, we are using mass
spectrometry to identify binding partners in cultured cells. Our
long-term goals are to understand the functions of the human TPR
proteome and to develop therapies for diseases caused by defects in TPR
signaling.
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Chinkers, M. PP5: the TPR phosphatase. Trends in Current Genetics, in press. |
