Crystal structure of p14TCL1, an oncogene product involved in T-cell prolymphocytic leukemia, reveals a novel β-barrel topology

Background: Chromosome rearrangements are frequently involved in the generation of hematopoietic tumors. One type of T-cell leukemia, T-cell prolymphocytic leukemia, is consistently associated with chromosome rearrangements characterized by the juxtaposition of the TCRA locus on chromosome 14q11 and either the TCL1 gene on 14q32.1 or the MTCP1 gene on Xq28. The TCL1 gene is preferentially expressed in cells of early lymphoid lineage; its product is a 14 kDa protein (p14(TCL1)), expressed in the cytoplasm, p14(TCL1) has strong sequence similarity with one product of the MTCP1 gene, p13(MTCP1) (41% identical and 61% similar). The functions of the TCL1 and MTCP1 genes are not known yet. They have no sequence similarity to any other published sequence, including those of well-documented oncogene families responsible for leukemia, In order to gain a more fundamental insight into the role of this particular class of oncogenes, we have determined the three-dimensional structure of p14(TCL1). Results: The crystal structure of p14(TCL1) has been determined at 2.5 Angstrom resolution. The structure was solved by molecular replacement using the solution structure of p13(MTCP1), revealing p14(TCL1) to be an all-beta protein consisting of an eight-stranded antiparallel beta barrel with a novel topology. The barrel consists of two four-stranded beta-meander motifs, related by a twofold axis and connected by a long loop, This internal pseudo-twofold symmetry was not expected on basis of the sequence alone, but structure-based sequence analysis of the two motifs shows that they are related. The structures of p13(MTCP1) and p14(TCL1) are very similar, diverging only in regions that are either flexible and/or involved in crystal packing, p14(TCL1) forms a tight crystallographic dimer, probably corresponding to the 28 kDa species identified in solution by gel filtration experiments, Conclusions: Structural similarities between p14(TCL1) and p13(MTCP1) suggest that their (unknown) function may be analogous. This is confirmed by the fact that these proteins are implicated in analogous diseases, Their structure does not show similarity to other oncoproteins of known structure, confirming their classification as a novel class of oncoproteins.