Structural Analysis of TCL-1 and MTCP-1 Proteins

TCL-1和MTCP-1是一个新的人类基因家族的成员，参与T细胞恶性肿瘤和淋巴样细胞的增殖和/或生存。这些基因编码约14 kDa的蛋白质，有41%相同的氨基酸残基。人TCL-1、MTCP-1和小鼠TCL-1已在大肠杆菌中表达，并以毫克量纯化，用于结构分析。在2.0A分辨率下测定了MTCP-1的晶体结构。这种结构是一种独特的8股贝塔桶，带有一个短螺旋。TCL-1的结构非常相似，在所有常见的Calpha原子上的均方根偏差为1.7埃。这些结构信息正被用于定点突变，并设计蛋白质表面区域的多肽类似物，作为癌基因功能的潜在抑制剂。TCL-1和MTCP-1的突变形式将被表达、鉴定和结构分析，并与野生型蛋白进行比较。TCL-1和MTCP-1的相互作用蛋白和其他潜在的配体将通过结晶学和生物化学方法进行研究。我们将比较TCL-1和MTP-1蛋白的结构和功能。TCL-1和MTCP-1的抑制剂具有治疗低度恶性T细胞淋巴瘤和白血病的潜力。

TCL-1 and MTCP-1 are members of a novel family of human genes that are involved in T-ell malignancies and lymphoid proliferation and/or survival. These genes code for proteins of about 14 kDa molecular weight, that share 41% identical amino acid residues. Human TCL-1 and MTCP-1 and mouse TCL-1 have been expressed in E. coli and purified in milligram quantities for structural analysis. The crystal structure of MTCP-1 has been determined at 2.0 A resolution. The structure is a unique 8-stranded beta barrel with one short helix. The structure of TCL- 1 is very similar with a root mean square deviation of 1.7 angstrom on all common Calpha atoms. The structural information is being used for site- directed mutagenesis, and to design peptide analogs of surface regions of the proteins as potential inhibitors of oncogene function. Mutant forms of TCL-1 and MTCP-1 will be expressed, characterized and analyzed structurally in comparison to the wild type protein. Interacting proteins and other potential ligands of TCL-1 and MTCP-1 will be studied by crystallography and biochemical methods. The structures and functions of TCL-1 and MTP-1 proteins will be compared. Inhibitors of TCL-1 and MTCP-1 have potential for treatment for low-grade T-cell lymphomas and leukemias.