DE NOVO STRUCTURE OF IGA PROTEASE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 1975年，我们的合作者安德鲁·帕鲁特发现了IGA蛋白水解酶。这些酶是由链球菌属、奈瑟氏菌属、嗜血杆菌属、解脲支原体属、梭状芽胞杆菌属、线虫属和类杆菌属中具有重要医学意义的病原菌产生的几种不同类型的细菌内肽酶。每种酶由单一的、非糖基化的、水溶性的多肽链组成。所有的IgA蛋白对人免疫球蛋白IgA1都有明显的底物特异性。每种酶在重的多肽链铰链区裂解一个特定的多肽键。最令人感兴趣的是这些酶表现出的高选择性机制，使得高度同源的人免疫球蛋白不是底物。该酶很大(110 KDa)，我们假设与典型的内肽酶不同，底物识别不是基于初级共识序列。相反，我们认为这些蛋白酶通过对IgA1分子的三维识别实现了高度的选择性，并随后介导了非结构铰链区的切割。这一机制类似于相扑蛋白水解酶。目前还没有关于这类酶的任何蛋白质的结构信息，因此目前的结构研究是非常重要的。

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.