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

ADAM蛋白酶主要是1型膜结合糖蛋白，是细胞表面蛋白外结构域加工的主要脱落酶，包括生长因子和细胞因子的潜在形式。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。ADAMs切割位点周围的氨基酸序列尚无共识，ADAMs如何识别靶分子的分子机制仍是一个谜。我们主要从蛇毒中提取几种ADAMs进行晶体学研究，因为蛇ADAMs是可溶性蛋白酶，没有跨膜区域，通常对不同的靶分子表现出高特异性。多激活酶具有激活凝血酶原的活性。我们确定了多激活酶外域的晶体结构，并讨论了多激活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.