In silico modeling of the evolution of TACC protein function
The protein and genomic structure of the present day TACC family members suggests that the function of the ancestral TACC protein was mediated solely through the interactions of the conserved TACC domain. Using an in silico protein-protein interaction model based upon known mitotic spindle and centrosomal components, we have previously predicted a number of additional interactions that could be conserved between a functional TACC homologue in yeast, spc-72, and one or more human TACC proteins [21]. Thus, it is known that all the TACC proteins examined to date interact, via the TACC domain, with the microtubule/centrosomal proteins of the stu2/msps/ch-TOG family [5,6,22-24], and with the Aurora kinases [20,21,25]. These interactions are required for the accumulation of the D-TACC, spc72, ceTAC1 and TACC3 proteins to the centrosome [5,6,22-24]. Hence, this functional interaction with the centrosome and mitotic spindle is likely to represent the ancient, conserved function of the TACC family. However, it is apparent that the human TACC proteins also differ in their ability to interact with the Aurora kinases. For instance, TACC1 and TACC3 interact with Aurora A kinase, whereas TACC2 interacts with Aurora C kinase [21], suggesting a degree of functional specialization in the derivatives of the ancestral chordate TACC, after the radiation of the vertebrate TACC genes.
The localization of the vertebrate TACC proteins in the interphase nucleus [15,26,27] suggests that they have additional functions outside their ancient role in the centrosome and microtubule dynamics. Thus, it seems likely that TACC family members in protostomes and deuterostomes have integrated new unique functions as the evolving TACC genes acquired additional exons. The results of the pilot large-scale proteomic analysis in C. elegans and D. melanogaster provide further suggestive evidence to this functional evolution. Yeast two hybrid analysis indicates that ceTAC directly binds to C. elegans lin15A, lin36 and lin37 [28]. These proteins bridge ceTAC to other elements of the cytoskeleton and microtubule network, as well as to components of the ribosome, the histone deacetylase chromatin remodeling machinery such as egr-1 and lin-53 (the C. elegans homologues of the human MTA-1 and RbAP48), and to transcription factors such as the PAL1 homeobox and the nuclear hormone receptor nhr-86 [28] (Fig. 6A). Similarly, large scale proteomics [29] has shown that Drosophila TACC interacts with two proteins, the RNA binding protein TBPH and CG14540 (Fig. 6B), and thus indirectly with the Drosophila SWI/SNF chromatin remodeling complex and DNA damage repair machinery. Significantly, the ceTAC protein has also recently been implicated in DNA repair through its direct interaction with the C. elegans BARD1 orthologue [30]. It should be noted that a number of interactions with the TACC proteins from these organisms have probably been missed by these large scale methods, including the well documented direct interactions with the aurora kinases and the stu2/msps/ch-TOG family.
Figure 6  Functional evolution of the TACC proteins modeled in C. elegans and D. melanogaster. (A). C. elegans interaction map shows empirically defined interactions of ceTAC, and extrapolated interactions defined by [28]. (B): Using the BIND database [29], DTACC directly binds to TBPH and CG14540, and thus indirectly to chromatin remodeling complexes (SWI/SNF and histone acetyltransferases), DNA damage repair machinery (via RAD23), and RNA splicing, transport and translational machinery. (C): Predicted interaction map for vertebrate TACCs, based upon ceTAC, suggests an indirect interaction with the nuclear hormone receptor RXRβ. It is also of interest that this predicts a functional interaction with the LDB family, members of which are also found in TACC containing paralogous segments noted in Figs 2, 3 and Additional file 1. (D): Predicted TACC interaction map based upon DTACC. (E): Vertebrate TACC interactions identified to date. ? denotes uncertainty over the identity of a functional vertebrate homologue. In C, D and E, '*' denotes one or more members of the TACC or Aurora kinase family. Because of the evolutionary conservation of the TACC domain, we would predict that some of the functional interactions seen in C. elegans and D. melanogaster would be observed in higher animals. Phylogenetic profiling from these interaction maps suggests two similar sets of predicted interactions for vertebrate TACCs (Fig. 6C and 6D). Strikingly, however, the C. elegans specific proteins lin15A, lin36 and lin37 do not have readily discernible homologues in vertebrates or Drosophila, although the presence of a zinc finger domain in lin36 may suggest that this protein is involved directly in transcription or perform an adaptor role similar to LIM containing proteins. For the DTACC interacting proteins, TBPH corresponds to TDP43, a protein implicated in transcriptional regulation and splicing [31,32]. However, the assignment of the human homologue of CG14540 is less clear, with the closest matches in the human databases corresponding to glutamine rich transcription factors such as CREB and the G-box binding factor.