DE NOVO STRUCTURE OF IGA PROTEASE

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来源获得了主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 伊加蛋白酶是由我们的合作者Andrew Palut于1975年发现的。这些酶是由链球菌属、奈瑟氏球菌属、嗜血杆菌属、脲原体属、梭菌属、二氧化碳噬纤维菌属和拟杆菌属中的医学上重要的病原菌产生的几种不同蛋白酶类型的细菌内肽酶。每种酶由单一的、非糖基化的、水溶性多肽链组成。所有伊加蛋白酶对人免疫球蛋白IgA 1具有明显的底物特异性。每种酶切割重多肽链铰链区中的单个特异性肽键。最令人感兴趣的是这些酶表现出的高选择性机制，使得高度同源的人IgA 2免疫球蛋白不是底物。 这种酶很大（110 kDa），我们假设与典型的内肽酶不同，底物识别不是基于一级共有序列。 相反，我们认为，这些蛋白酶实现其高度的选择性，通过3-D识别的IgA 1分子，随后介导切割的非结构化铰链区。 这一机制与SUMO蛋白酶相似。 目前还没有关于这类蛋白酶的任何蛋白质的结构信息，因此目前的结构研究非常重要。

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. IgA proteases were discovered in 1975 by our collaborator Andrew Palut. These enzymes are bacterial endopeptidases of several different protease types produced by medically important pathogenic bacteria in the genera Streptococcus, Neisseria, Haemophilus, Ureaplasma, Clostridia, Capnocytophaga and Bacteroides. Each enzyme consists of a single, non-glycosylated, water soluble polypeptide chain. All IgA proteases have pronounced substrate specificity for human immunoglobulin IgA1. Each enzyme cleaves a single, specific peptide bond in the heavy polypeptide chain hinge region. Of extreme interest is the mechanism of high selectivity exhibited by these enzymes such that the highly homologous human IgA2 immunoglobulin is not a substrate. The enzyme is large (110kDa) and we postulate that unlike typical endopeptidases, substrate recognition is not based upon a primary consensus sequence. In contrast we believe that these proteases achieve their high degree of selectivity via 3-D recognition of the IgA1 molecule and subsequently mediate cleavage in the unstructured hinge region. This mechanism is similar to that of SUMO-protease. There is currently no structural information on any proteins of this class of proteases and therefore the current structural investigation is of great importance.