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细胞增殖和/或生存。这些基因编码分子量约为14 kDa的蛋白质，其中41%的氨基酸残基相同。人TCL-1和MTCP-1以及小鼠TCL-1已在大肠杆菌中表达，并以毫克量纯化用于结构分析。MTCP-1的晶体结构在2.0 A分辨率下被确定。结构是一个独特的8股贝塔桶与一个短螺旋。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。结构信息被用于定点诱变，并设计蛋白质表面区域的肽类似物作为癌基因功能的潜在抑制剂。与野生型蛋白相比，TCL-1和MTCP-1的突变形式将被表达、表征和结构分析。通过晶体学和生化方法研究TCL-1和MTCP-1的相互作用蛋白和其他潜在配体。比较TCL-1和MTP-1蛋白的结构和功能。TCL-1和MTCP-1抑制剂具有治疗低级别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.