Crystal structure of MTCP-1: implications for role of TCL-1 and MTCP-1 in T cell malignancies

Abstract

Two related oncogenes, TCL-1 and MTCP-1, are overexpressed in T cell prolymphocytic leukemias as a result of chromosomal rearrangements that involve the translocation of one T cell receptor gene to either chromosome 14q32 or Xq28. The crystal structure of human recombinant MTCP-1 protein has been determined at 2.0 A resolution by using multiwavelength anomalous dispersion data from selenomethionine-enriched protein and refined to an R factor of 0.21. MTCP-1 folds into a compact eight-stranded beta barrel structure with a short helix between the fourth and fifth strands. The topology is unique. The structure of TCL-1 has been predicted by molecular modeling based on 40% amino acid sequence identity with MTCP-1. The identical residues are clustered inside the barrel and on the surface at one side of the barrel. The overall structure of MTCP-1 superficially resembles the structures of proteins in the lipocalin family and calycin superfamily. These proteins have diverse functions, including transport of retinol, fatty acids, chromophores, pheromones, synthesis of prostaglandin, immune modulation, and cell regulation. However, MTCP-1 differs in the topology of the beta strands. The structural similarity suggests that MTCP-1 and TCL-1 form a unique family of beta barrel proteins that is predicted to bind small hydrophobic ligands and function in cell regulation.

Figure 1

Structural alignment of amino acid sequences of human recombinant MTCP-1 and TCL-1. The secondary structure of MTCP-1 is indicated below the sequence by arrows for β strands A to H and a thick line for the helix. The residues that form the internal hydrophobic core of the structure are indicated by ∗.

Figure 2

Crystal structure of MTCP-1. A molscript (36) ribbon representation with arrows indicating β strands. Two orthogonal views are shown in A and B.

Figure 3

(A) Topology of the eight-stranded antiparallel β barrel of MTCP-1. β strands A to H are indicated by arrows and the helix by a cylinder. (B) Topology of the lipocalin fold. The β strands A to H are indicated by arrows, the α helix by a cylinder, and the amino-terminal 3₁₀ helix by an ellipse.

Figure 4

(A) The amino acid side chains of residues that are identical in TCL-1 and MTCP-1 are shown in red on the Cα backbone of the MTCP-1 structure (blue) looking into the β barrel in the same orientation as Fig. 2B. Electrostatic potential surface for MTCP-1 and TCL-1. The negative electrostatic potential energy surface contoured at 0.3 e/Å3 is shown in blue for the crystal structure of MTCP-1 and in red for the model of TCL-1. The black lines indicate the Cα backbone of MTCP-1 in the same view as Fig. 2A, showing the four longer strands crossing over the four shorter strands of the β barrel with the helix at the lower right side.