Tousseyn Thomas, Jorissen Ellen, Reiss Karina, Hartmann Dieter
Laboratory for Neuronal Cell Biology and Gene Transfer, Department for Human Genetics, K.U. Leuven and Flanders Interuniversity Institute for Biotechnology, Leuven/Flanders, Belgium.
Birth Defects Res C Embryo Today. 2006 Mar;78(1):24-46. doi: 10.1002/bdrc.20066.
"A disintegrin and metalloprotease" (ADAM) proteases form a still growing family of about 40 type 1 transmembrane proteins. They are defined by a common modular ectodomain architecture that combines cell deadhesion/adhesion and fusion motifs (disintegrin and cysteine-rich domains), with a Zn-protease domain capped by a large prodomain. Their ectodomain thus strikingly resembles snake venom disintegrin proteases, which by combined integrin blocking and extracellular proteolysis, can cause extensive tissue damage after snake bites. A surprisingly large proportion (13 ADAMs) is exclusively expressed in the male gonads, and only a minority can be found throughout all tissues. As predicted by their amino acid sequence, a major proportion of this family has not maintained a functional protease domain, most probably rendering them into pure adhesion and/or fusion proteins. For most ADAMs, the respective key function has remained elusive. Despite their overall conserved ectodomain structure, ADAMs appear to be subdivided into those with a predominant role in direct adhesion (e.g., ADAMs 1, 2, and 3) and those mainly acting as proteases (e.g., ADAMs 10 and 17). Only for a few of them are functions of more than one domain documented (e.g., ADAM9 in cell fusion and proteolysis). Several ADAMs exist in both membrane-resident and secreted isoforms; the functional significance of this dichotomy is in most cases still unclear. Knockout phenotypes have been informative only in a few cases (ADAMs 1, 2, 10, 12, 15, 17, and 19) and are mainly related to their protease function. A common denominator of ADAM-mediated proteolysis is the ectodomain shedding of a broad spectrum of substrates, including paracrine growth factors like epidermal growth factor receptor (EGFR) ligands, cell adhesion molecules like CD44 or cadherins, and the initiation of regulated intramembrane proteolysis (RIP), whereby the transmembrane fragment of the respective substrate is further cleaved by an intramembrane cleaving protease to release an intracellular domain acting as a nuclear transcription regulator. Most ADAMs feature a significant overlap of substrate specificities, explaining why an inactivation of individual ADAMs only rarely causes major phenotypes.
“解聚素和金属蛋白酶”（ADAM）蛋白酶构成了一个仍在不断壮大的家族，包含约40种1型跨膜蛋白。它们由一种常见的模块化胞外结构域架构所定义，该架构将细胞去黏附/黏附及融合基序（解聚素和富含半胱氨酸的结构域）与一个由大的前结构域封闭的锌蛋白酶结构域相结合。因此，它们的胞外结构域与蛇毒解聚素蛋白酶惊人地相似，后者通过整合素阻断和细胞外蛋白水解的共同作用，可在蛇咬后造成广泛的组织损伤。令人惊讶的是，很大一部分（13种ADAM）仅在雄性性腺中表达，在所有组织中仅能发现少数几种。正如根据其氨基酸序列所预测的那样，该家族的大部分成员并未保留功能性蛋白酶结构域，很可能使其变成了单纯的黏附蛋白和/或融合蛋白。对于大多数ADAM而言，其各自的关键功能仍不明确。尽管它们的胞外结构域总体上保守，但ADAM似乎可分为在直接黏附中起主要作用的那些（如ADAM1、2和3）以及主要作为蛋白酶起作用的那些（如ADAM10和17）。只有少数几种ADAM的多个结构域功能得到了证实（如ADAM9在细胞融合和蛋白水解方面的功能）。几种ADAM同时存在膜结合型和分泌型异构体；在大多数情况下，这种二分法的功能意义仍不清楚。基因敲除表型仅在少数情况下（ADAM1、2、10、12、15、17和19）提供了有用信息，且主要与其蛋白酶功能相关。ADAM介导的蛋白水解的一个共同特征是多种底物的胞外结构域脱落，这些底物包括旁分泌生长因子如表皮生长因子受体（EGFR）配体、细胞黏附分子如CD44或钙黏蛋白，以及调节性膜内蛋白水解（RIP）的起始，即相应底物的跨膜片段被膜内裂解蛋白酶进一步切割，以释放作为核转录调节因子的细胞内结构域。大多数ADAM具有显著重叠的底物特异性，这解释了为何单个ADAM的失活很少导致主要表型。
