CD147-乳酸转运蛋白复合体调控底物跨膜转运及肿瘤微环境与代谢的结构基础

CD147是属于免疫球蛋白超家族的单次跨膜蛋白，广泛高表达于多种肿瘤细胞，被视为肿瘤标志物及肿瘤治疗的重要靶标。乳酸转运蛋白作为多次跨膜的转运载体，可将糖酵解产生的乳酸转运到胞外，调控肿瘤代谢及维持酸性微环境稳态，是肿瘤治疗的另一重要靶标。CD147可与乳酸转运蛋白结合，协助其转位至肿瘤细胞膜，调控其在膜上的表达水平及活性，促进肿瘤的增殖、侵袭、转移及血管生成。研究该复合体的功能及活性调控的分子机制有助于深入理解肿瘤发生及致病机理，为癌症治疗及药物研发提供线索。.真核乳酸转运蛋白及其与CD147复合物的结构尚未见报道，仅有CD147的部分胞外结构域及其与抗体复合物的结构被解析。为揭示该复合物转运乳酸、调控肿瘤代谢与微环境的分子机理，我们开展了结构与功能研究，制备了多种不同亚型和功能态的复合物样品，投入结晶筛选和冷冻电镜制样优化。已获得可衍射晶体，样品优化和数据采集正在稳步推进中。

CD147, a single pass transmembrane protein, is a member of immunoglobulin superfamily that is found to be over-expressed in many cancer cells. It has been considered as a tumor biomarker and target of cancer diagnosis/therapy. As multiple transmembrane-carriers, lactate transporters efflux glycolytic lactate across the plasma membrane into the extracellular space, which modulate the tumor metabolism and play an important role in pH homeostasis in the tumor microenvironment. Therefore, it becomes another important target of cancer diagnosis/therapy. As a chaperone, CD147 binds to lactate transporter, facilitates the carrier to localize into the plasma membrane of tumor cells, modulates its expression level and activity, and hence promoting tumor proliferation, invasion, metastasis and angiogenesis. Research on the protein-complex activity/function and its molecular regulation mechanism benefits to our understanding of cancer pathogenesis, and also facilitates tumor therapy and the drug development. .Currently, no any 3-D structure is reported on eukaryotic lactate transporter or its complex with CD147, except several reported domain-structures of apo-CD147 or CD147-antibody complex. To elucidate the molecular regulating mechanism of the substrate transport by the complex, tumor metabolism and the acidic microenvironment，we have lunched a study on the structure and function of the complexes. So far, our preliminary study has already made some solid progress. We have obtained high-quality samples with several different isoforms or in different functional states. Crystallization experiments have harvested X-ray diffractable crystals, while optimization of the cryoEM-sample preparation has shown several promising routines. It is expectable to make breakthrough on the project.