Haem recognition by a Staphylococcus aureus NEAT domain
Haem recognition by a Staphylococcus aureus NEAT domain
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DOI：
10.1111/j.1365-2958.2006.05502.x
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发表时间：
2007-01-01
影响因子：
3.6
通讯作者：
Murphy, Michael E. P.
中科院分区：
文献类型：
--
作者：
Grigg, Jason C.;Vermeiren, Christie L.;Murphy, Michael E. P.
成功的病原体已经发展出在极端水平的铁限制下茁壮成长的机制。血红素铁是人体内最大的铁储存库，是某些细菌病原体的重要铁来源。NEAT（NEAr转运蛋白）结构域仅存在于革兰氏阳性细菌的细胞表面蛋白家族中。许多含有NEAT结构域的蛋白质，包括金黄色葡萄球菌中的IsdA，与血红素结合有关。在这里，我们发现在S.与野生型相比，当在含有血红素作为唯一铁源的培养基中生长时，金黄色葡萄球菌的IsdA增强生长，并且IsdA的失活突变体具有生长缺陷。此外，IsdA的haem结合特性包含在NEAT结构域中。解出了apo-IsdA NEAT结构域和与血红素复合的晶体结构，并揭示了具有大的疏水血红素结合口袋的网格蛋白衔接子样β-夹心折叠。血红素与分子表面的丙酸酯基团结合，铁仅与Tyr（166）配位。Tyr（166）和Tyr（170）的酚基形成H-键，其可在调节血红素结合和释放中起作用。IsdA结构-序列比对分析表明，Tyr（166）的保守性是NEAT结构域与血红素结合的预测因子。
Successful pathogenic organisms have developed mechanisms to thrive under extreme levels of iron restriction. Haem-iron represents the largest iron reservoir in the human body and is a significant source of iron for some bacterial pathogens. NEAT (NEAr Transporter) domains are found exclusively in a family of cell surface proteins in Gram-positive bacteria. Many NEAT domain-containing proteins, including IsdA in Staphylococcus aureus, are implicated in haem binding. Here, we show that overexpression of IsdA in S. aureus enhances growth and an inactivation mutant of IsdA has a growth defect, compared with wild type, when grown in media containing haem as the sole iron source. Furthermore, the haem-binding property of IsdA is contained within the NEAT domain. Crystal structures of the apo-IsdA NEAT domain and in complex with haem were solved and reveal a clathrin adapter-like beta-sandwich fold with a large hydrophobic haem-binding pocket. Haem is bound with the propionate groups directed at the molecular surface and the iron is co-ordinated solely by Tyr(166). The phenol groups of Tyr(166) and Tyr(170) form an H-bond that may function in regulating haem binding and release. An analysis of IsdA structure-sequence alignments indicate that conservation of Tyr(166) is a predictor of haem binding by NEAT domains.