Key determinants of receptor activation in the agr autoinducing peptides of Staphylococcus aureus
Key determinants of receptor activation in the agr autoinducing peptides of Staphylococcus aureus
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DOI：
10.1021/bi026049u
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发表时间：
2002-08-06
期刊：
影响因子：
2.9
通讯作者：
Novick, RP
中科院分区：
文献类型：
--
作者：
Lyon, GJ;Wright, JS;Novick, RP
葡萄球菌的发病机制是由一个双组分群体感应系统（agr）调控的，该系统在一种自编码的自诱导肽（AIP）与受体组氨酸激酶（AgrC）结合时被激活。AlPs由一个硫内酯大环和一个外环“尾巴”组成，两者对功能都很重要。在本报告中，完成了金黄色葡萄球菌四个已知agr特异性群中独特的阿尔卑斯山脉的表征，并分析了四个阿尔卑斯山脉对AgrC激活的跨组抑制作用。本研究得出以下结论：(i)天然硫内酯大环和尾部对于AlPs的完全激活是必要和充分的，而aip - 1大环本身是部分激动剂。（ii）原生n端不那么重要，因为AIP-I的n端可以被修饰而不影响生物活性，而AIP-III的n端则不能。（iii）环和尾在不同的AlPs中可能具有不同的功能。因此，I组和IV组的alp在单个（内环）残基上有所不同，这是这两组AIP特异性的决定因素，对功能至关重要。然而，AIP-II中类似的关键残基是外环残基。（iv）交叉抑制比激活更能容忍序列和结构多样性，这表明AlPs与同源受体的相互作用不同于与异源受体的相互作用。(v)嵌合肽，其中尾部和大环被切换，不激活，而是抑制受体的激活。这些数据表明，在一个模型中，激活和抑制涉及到每个受体的配体结合口袋内不同的结合方向。
Staphylococcal pathogenesis is regulated by a two-component quorum-sensing system, agr, activated upon binding of a self-coded autoinducing peptide (AIP) to the receptor-histidine kinase, AgrC. The AlPs consist of a thiolactone macrocyle and an exocyclic "tail", both of which are important for function. In this report, characterization of the unique AlPs from the four known agr specificity groups of Staphylococcus aureus has been completed, along with analysis of cross-group inhibition of AgrC activation by each of the four AlPs. The following conclusions have been drawn: (i) The native thiolactone macrocyle and tail are necessary and sufficient for full activation by the AlPs, whereas the AIP-I macrocycle alone is a partial agonist. (ii) The native N-terminus is less critical, as that of AIP-I can be modified without affecting bioactivity, although that of AIP-III cannot. (iii) The ring and tail may function differently in different AlPs. Thus the group I and IV AlPs differ at a single (endocyclic) residue, which is the determinant of AIP specificity for these two groups and is essential for function. A similarly critical residue in AIP-II, however, is exocyclic. (iv) Cross-inhibition is more tolerant of sequence and structural diversity than is activation, suggesting that the AlPs interact differently with cognate than with heterologous receptors. (v) Chimeric peptides, in which the tails and macrocycles are switched, do not activate and instead inhibit receptor activation. These data suggest a model in which activation and inhibition involves different binding orientations within the ligand binding pocket of each receptor.