A NOVEL REGULATORY MECHANISM OF A HUMAN LYMPHOCYTE METALLOPROTEASE

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。所列机构为 中心，不一定是研究者的机构。 亚当斯（一种去整合素和金属蛋白酶）是多结构域蛋白质，其参与广泛的生物事件，例如受精、神经发生和免疫应答以及疾病状态，例如肿瘤发作/进展、慢性炎症和阿尔茨海默氏症。 两个定义域结构，一个解整合素和金属蛋白酶，已建立亚当斯作为一类新的蛋白质，同时具有粘合剂和蛋白水解性质。已经在各种哺乳动物物种中鉴定了33种亚当斯，其中只有三分之一具有指示功能性金属蛋白酶的共有位点。尽管大多数鉴定的ADAM成员缺乏蛋白水解活性，但这些无活性亚当斯的生物学作用尚不清楚。 活性ADAM金属蛋白酶是充分表征的胞外域脱落酶，其能够通过从细胞表面专性加工/切割生物活性因子（例如细胞因子和生长因子）来调节细胞外信号。活性和非活性ADAM成员都能够通过其去整合素结构域介导整合素依赖性细胞粘附。蛋白水解和粘附特异性的相互依赖性在很大程度上仍然不确定。基于目前的模型，非蛋白水解的ADAM结构域管理蛋白酶的特异性，这个建议的目的是描绘无活性的亚当斯的作用，影响ADAM介导的脱落。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. ADAMs (a disintegrin and metalloprotease) are multidomain proteins that participate in a wide array of biological events such as fertilization, neurogenesis, and immune response as well as disease states such as tumor onset/progression, chronic inflammation, and Alzheimer's. The two defining domain structures, a disintegrin and metalloprotease, have established ADAMs as a novel class of proteins possessing both adhesive and proteolytic properties. Thirty-three ADAMs have been identified in various mammalian species with only one third possessing a consensus site indicative of a functional metalloprotease. Even though the majority of identified ADAM members lack proteolytic activity, the biological role of these inactive ADAMs is poorly defined. Active ADAM metalloproteases are well-characterized ectodomain sheddases capable of regulating extracelluar signals by obligate processing/cleavage of bioactive factors (e.g. cytokines and growth factors) from the cell surface. Both active and inactive ADAM members are capable of mediating integrin-dependent cell adhesion through their disintegrin domains. The interdependence of the proteolytic and adhesive specificities remains largely undefined. Based upon current models that nonproteolytic ADAM domains govern protease specificity, this proposal aims to delineate the role of inactive ADAMs in influencing ADAM-mediated shedding.