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，并作为主要的脱落酶用于加工细胞表面蛋白质胞外域，包括潜在形式的生长因子和细胞因子。亚当斯在正常发育和形态发生中起关键作用，并与多种疾病有关，包括癌症和阿尔茨海默病。在被亚当斯切割的位点周围没有共有的氨基酸序列，并且亚当斯如何识别靶分子的分子机制仍然难以捉摸。我们专注于从蛇毒中的几个亚当斯晶体学研究，因为蛇亚当斯是可溶性蛋白酶，没有跨膜区域，通常显示不同的靶分子的高特异性。从Echis multimantus中分离的多活化酶具有凝血酶原活化活性。我们已经确定了Multactivase的外部结构域的晶体结构，并讨论了凝血酶原识别Multactivase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.