Structure of signal peptide peptidase

描述(申请人提供)：多蛋白复合体伽马分泌酶蛋白分解淀粉样前体蛋白(APP)的膜内区域，进而形成阿尔茨海默病(AD)患者的斑块。γ-分泌酶的催化成分是膜内天冬氨酸蛋白酶(IAP)，称为早老素。早老素基因突变与家族性早发性AD直接相关。IAP家族的另一个已知成员是信号肽酶(SPP)，它的功能是在被信号肽酶切割后进一步降解残存的信号肽。关于单个SPP的生物化学和功能的知识才刚刚开始被阐明，在所有的生命王国中都有同源生物。早老素和SPP具有显著的序列相似性，强烈表明它们具有共同的结构和催化特征。因此，对更易处理的SPP的分子理解可能会影响早老素和伽马分泌酶的药物设计。这一建议的目标是表达、表征和解决极端细菌SPP的晶体结构，该同系物本身具有过渡态类似物抑制剂和底物模拟物。此外，候选药物将在硅胶中进行筛选。这种膜内蛋白水解酶的第一种结构将提供对膜内蛋白分解的生物化学的关键洞察，并使基于结构的AD药物开发和筛选成为可能。

DESCRIPTION (provided by applicant): The multiprotein complex gamma-secretase proteolytically cleaves the intramembrane region of amyloid precursor protein (APP), which in turn forms the plaques found in Alzheimer's disease (AD) patients. The catalytic component of gamma-secretase is the intramembrane aspartyl protease (IAP) called presenilin. Mutations in presenilin are directly linked to familial early-onset AD. Another known member of the IAP family is signal peptide peptidase (SPP), which functions to further proteolyze remnant signal peptides after they have been cleaved by signal peptidase. Knowledge of the biochemistry and function of individual SPPs are only beginning to be elucidated, and homologues are found in all kingdoms of life. Presenilin and SPP exhibit significant sequence similarity, strongly suggesting they share structural and catalytic features. Thus, a molecular understanding of the more tractable SPP will likely impact drug design for presenilin and gamma- secretase. The goal of this proposal is to express, characterize, and solve the crystal structure of an extremophilic bacterial SPP ortholog by itself, with a transition-state analog inhibitor and with a substrate mimic. In addition, drug candidates will be screened in silico. This first structure of an intramembrane protease will provide critical insight into the biochemistry of intramembrane proteolysis and enable structure- based AD drug development and screening.