Crystal structure of P4tcl1, an oncogene product involved in T-cell prolymphocytic leukemia, reveals a nolve beta-barrel topology
Résumé
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 Å resolution. The structure was solved by molecular replacement using the solution structure of p13 MTCP1 , revealing p14 TCL1 to be an all-β protein consisting of an eight-stranded antiparallel β barrel with a novel topology. The barrel consists of two four-stranded β-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.