Structural study for understanding the molecular mechanism of ectodomain shedding by ADAM family proteinases

ADAM蛋白水解酶主要是1型膜结合糖蛋白，是细胞表面蛋白胞外结构域加工的主要脱水酶，包括潜在形式的生长因子和细胞因子。ADAMS在正常发育和形态发生中发挥关键作用，并与包括癌症和阿尔茨海默病在内的几种疾病有关。亚当斯切割的位点周围没有一致的氨基酸序列，亚当斯如何识别目标分子的分子机制仍然难以捉摸。我们主要针对蛇毒中的几种ADAM进行结晶学研究，因为蛇ADAM是没有跨膜区域的可溶性蛋白水解酶，通常对不同的靶分子表现出高度的特异性。从马尾藻中分离得到的多活化酶具有凝血酶原激活活性。我们测定了多活化酶外切结构域的晶体结构，并讨论了多活化酶识别凝血酶原裂解的分子机制。

ADAM proteinases are mostly type-1 membrane-bound glycoproteins and function as major sheddases for the processing of cell-surface-protein ectodomains, including the latent forms of growth factors and cytokines. ADAMs play key roles in normal development and morphogenesis and are associated with several diseases, including cancer and Alzheimer's disease. There are no consensus amino acid sequences around the sites cleaved by ADAMs and the molecular mechanism how ADAMs recognize the target molecules remains elusive. We focused on several ADAMs from snake venoms for crystallographic studies because snake ADAMs are soluble proteinases without membrane-spanning regions and usually display high specificity for distinct target molecules. Multactivase isolated from Echis multimantus has a prothrombin-activating activity. We have determined a crystal structure of the exosite domain of Multactivase and discussed the molecular mechanism of prothrombin recognition for cleavage by Multactivase.