Assembly of E.Coli Outer Membrane Proteins

描述（由申请人提供）：蛋白质折叠和组装是所有活细胞正常运作必须正确发生的核心生物过程。许多毁灭性的人类疾病，包括神经退行性阿尔茨海默病和朊病毒疾病，都是蛋白质折叠和组装紊乱的结果。相对大量的细胞活动致力于确保蛋白质的正确折叠和组装。在错误折叠的情况下，蛋白质被驱动到聚集和降解途径。错误折叠蛋白质的降解是至关重要的，因为它们可能形成有毒的聚集体，从而干扰正常的细胞功能。因此，减少聚集（伴侣和折叠酶）或去除聚集（蛋白酶）的组装因子是互补的细胞活动，受细胞蛋白质折叠状态的调节。

DESCRIPTION (provided by applicant): Protein folding and assembly are central biological processes that must occur correctly for the proper functioning of all living cells. Many devastating human diseases, including neurodegenerative Alzheimer and prion diseases, are the consequence of disarrayed protein folding and assembly. A relatively large amount of cellular activity is dedicated to ensure the correct folding and assembly of proteins. In the event of misfolding, proteins are driven to aggregation and degradation pathways. Degradation of misfolded proteins is crucial because they may form toxic aggregates, which can interfere with normal cellular functions. Assembly factors that minimize aggregation (chaperones and foldases) or remove aggregates (proteases) are therefore complementary cellular activities that are regulated in response to the protein-folding status of the cell. Studying the assembly of membrane proteins has been a challenging task owing to their complex folding behavior. However, a recent explosion in the structural resolution of many membrane proteins, including those included in this study, has given a renewed impetus to the field of membrane protein biogenesis. The proposed research is directed at understanding the assembly of a unique OMP of E. coli, TolC, which folds into a novel three-dimensional structure. The TolC protein carries out several medically and physiologically important functions, including antibiotic efflux and toxin secretion. This research will identify and characterize intragenic and extragenic factors that contribute to TolC's assembly into trimeric barrels composed of alpha-helices and beta-strands. These aspects will be studied through exploiting genetic, molecular, and biochemical methods. The available data show that TolC follows an assembly pathway distinct from all other OMPs studied so far, thus providing an opportunity to uncover novel principles governing OMP targeting and assembly.