CRYSTALLOGRAPHIC ANALYSIS OF A BACTERIAL MEMBRANE PROTEASE

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。次级项目的主要支助 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 为子项目列出的总成本可能 表示子项目使用的中心基础设施的估计数量， NCRR赠款不直接向子项目或子项目工作人员提供资金。 导致家族性阿尔茨海默病（AD）的大多数显性突变存在于两个同源早老素（PS1，PS2）基因中。 目前对早老素蛋白酶家族的结构和机制知之甚少。 我们计划解决早老素的细菌同系物的晶体结构。 结构数据可能会揭示一些重要的问题：（i）早老素如何切割似乎埋在膜中的肽键？ (ii)在PS1和PS2的一级序列中发现了疾病突变。 它们是如何改变切割特异性，使其更有利于毒性更大的A 42的？

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Most dominant mutations that cause Familial Alzheimer's Disease (AD) are found in the two homologous presenilin (PS1, PS2) genes. Little is currently known about the structure and mechanism for the presenilin family of proteases. We plan to solve the crystal structure of a bacterial homolog of presenilin. The structural data is likely to shed light on a number of important questions: (i) How does presenilin cleave peptide bonds that appear to be buried in the membrane? (ii) The disease mutations are found throughout the primary sequence pf PS1 and PS2. How do they all alter the cleavage specificity in favor of the more toxic A¿42?