Surface Protein Anchoring in Gram Positive Bacteria

革兰氏阳性细菌中的表面蛋白锚定

• 批准号: 6986217
• 负责人: Olaf Schneewind
• 金额: $ 36.74万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6986217
• 关键词: Corynebacterium diphtheriae; Staphylococcus aureus; aminoacyltransferase; bacteria infection mechanism; bacterial proteins; binding proteins; cell wall; genetic screening; gram positive bacteria; host organism interaction; inhibitor /antagonist; laboratory mouse; laboratory rabbit; mass spectrometry; membrane proteins; membrane transport proteins; peptidases; peptidoglycan; pilus; protein structure function; protein transport; transpeptidation; Corynebacterium diphtheriae; Staphylococcus aureus; aminoacyltransferase; bacteria infection mechanism; bacterial proteins; binding proteins; cell wall; genetic screening; gram positive bacteria; host organism interaction; inhibitor /antagonist; laboratory mouse; laboratory rabbit; mass spectrometry; membrane proteins; membrane transport proteins; peptidases; peptidoglycan; pilus; protein structure function; protein transport; transpeptidation

DESCRIPTION (provided by applicant): Gram-positive bacteria employ surface proteins to bind to host tissues, to escape from innate and acquired immune responses, or to invade host epithelia and immune cells. Surface proteins of Staphylococcus aureus are anchored to the cell wall envelope by a mechanism requiring both an N-terminal signal peptide and a C-terminal sorting signal with an LPXTG motif. Sortase A (SrtA), a membrane anchored transpeptidase, cleaves the LPXTG motif of the sorting signal between its threonine (T) and glycine (G) residues and tethers the C-terminal carboxyl group of surface proteins to the amino group of cell wall cross-bridges within the lipid II peptidoglycan precursor. The product of this reaction is subsequently incorporated into the cell wall envelope via the transpeptidation and transglycosylation reactions of peptidoglycan synthesis. S. aureus mutants lacking the srtA gene display significant defects in the pathogenesis of animal disease. The genome of S. aureus encodes two sortase genes, each of which provide distinct anchoring mechanisms for defined sets of surface proteins. The genomes of some gram-positive microbes harbor additional sortase genes that provide for the assembly of pili on the surface of C. diphtheria, E. faecalis, S. agalactiae, A. naeslundii, C. perfringens and perhaps other pathogens. Experimental work in this research proposal tests three general hypotheses: (i) Inhibitors of sortases may be useful for the treatment of bacterial infectious diseases, (ii) The genes and gene products involved in surface protein transport and anchoring to the cell wall envelope may be identified using systematic genetic analysis, (iii) Pilus formation in gram-positive bacteria involves three unique sortase-mediated reactions that can be characterized by revealing the molecular structures of trans-peptidation reaction products.

描述（由申请人提供）：革兰氏阳性细菌采用表面蛋白与宿主组织结合，逃脱先天和获得的免疫反应，或者入侵宿主上皮细胞和免疫细胞。金黄色葡萄球菌的表面蛋白通过需要N末端信号肽和具有LPXTG基序的C末端分类信号的机制固定在细胞壁包膜上。分类酶A（SRTA）是一种锚定过肽酶的膜，将其苏氨酸（T）和甘氨酸（G）残基之间的分类信号的LPXTG图案切开，并将表面蛋白的C末端羧基tethers tethers tethers tethers tethers carbosyl cart-lipid cross-bride cross-lipid cross-ii ii peptiDogildogildogildogimelogiLscun中的氨基壁盘互互桥。随后，通过肽聚糖合成的转肽和转糖基化反应将该反应的产物掺入细胞壁包膜中。缺乏SRTA基因的金黄色葡萄球菌突变体在动物疾病的发病机理中显示出明显的缺陷。金黄色葡萄球菌的基因组编码了两个排序酶基因，每个分子基因为定义的表面蛋白集提供了独特的锚定机制。某些革兰氏阳性微生物的基因组具有其他排序酶基因，这些基因提供了在白喉，大肠杆菌，S。Agalactiae，A。Naeslundii，C。perfringens和其他病原体的表面上组装pili的基因。这项研究提案中的实验性工作测试了三个一般假设：（i）分类酶的抑制剂可能有助于治疗细菌感染性疾病，（ii）使用系统的遗传分析（III II）涉及三种独特的细胞酶，可以鉴定出在细胞壁构造中所涉及的表面蛋白传输并锚定在细胞壁膜上的基因和基因产物。反肽反应产物的分子结构。