Trends in Biochemical Sciences
TPR proteins: the versatile helix
Section snippets
TPR structure
Owing to the amphiphilic nature of the predicted helices, it was originally proposed that the TPR would form some type of coiled-coil or helical-bundle structure, with ‘knobs into holes’ packing 1, 3. Sikorsky et al. identified a consensus sequence defined as the positions at which there is at least 40% occurrence of a single amino acid type 1, 2. Box 1 provides a description of the structural and/or sequence preference of a TPR.
The first solved structure of a TPR was the three-TPR domain of
TPR and disease
There are an increasing numbers of reports that link the malfunctioning of a TPR-containing protein with human disease. In some cases, the mutations are within the TPR domain; in others, the involvement of the TPR domain is less clear. A complete review of this area is beyond the scope of this review, but a few interesting examples are given in the following section.
A homozygous nonsense mutation in the TPR region of the gene encoding aryl-hydrocarbon-interacting-protein-like 1 (AIPL1) causes
TPR design
TPR domains are found in almost all organisms and perform a host of different functions. The TPR can be considered a scaffold: the fold is defined by the consensus sequence onto which functionally specific residues can be grafted, enabling recognition of diverse range of target proteins. Recently, a newly designed protein based on a statistical analysis of TPR sequences has been shown to fold into a particularly stable TPR motif [18] (Box 2). This molecule represents a versatile scaffold in
TPR function: genomic repertoires
TPR domains mediate protein–protein interactions, and, in a few cases, the exact features of the target protein that are recognized, and the specificity of the interaction are well established (Box 3). However, in the majority of cases, either the target protein itself or the region of the target protein that is recognized might be unknown.
Figure 2 shows a selection of TPR proteins with different arrangements and combinations of TPR motifs; in these examples, the binding partner is known. The
The complete repertoire of TPR proteins in yeast
Because the complete TPR repertoire of a single organism can be predicted, the role of TPR proteins can be viewed from a genome-wide context. The smallest and best-studied eukaryotic organism of known sequence is yeast. Table 1 lists all of the predicted TPR proteins in yeast, including the predicted number of repeats, and what – if anything – is known about the function of the protein. Results presented in several protein–protein interaction databases reveal that many of the proteins listed in
Concluding remarks
The apparently simple helical motif of a TPR functions in a variety of different proteins that are involved in a plethora of cellular processes. The basic function of TPR domains is to mediate protein–protein interactions, and this can be achieved in a variety of ways. The smallest functional unit that is widely used appears to be three tandem-TPR motifs. Binding residues are presented on the concave face of the repeat and bind with high specificity to the target peptide. The function and
Acknowledgements
L.D.D. was supported, in part, by a NATO-CNR fellowship. We thank Tommi Kajander, Aitzeber López Cortajarena and Chris Wilson for insightful comments and critical reading of the manuscript. We particularly thank Tommi Kajander for creating Box 3 Figure I. We also thank the referees for their suggestions, particularly G. Blatch for pointing out Ref. [19].
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