Biometals ( IF 4.1 ) Pub Date : 2022-11-23 , DOI: 10.1007/s10534-022-00466-6
Clement Chan 1 , Dixon Ng 1, 2 , Marie E Fraser 3 , Anthony B Schryvers 1
|
Iron is an essential element for various lifeforms but is largely insoluble due to the oxygenation of Earth’s atmosphere and oceans during the Proterozoic era. Metazoans evolved iron transport glycoproteins, like transferrin (Tf) and lactoferrin (Lf), to keep iron in a non-toxic, usable form, while maintaining a low free iron concentration in the body that is unable to sustain bacterial growth. To survive on the mucosal surfaces of the human respiratory tract where it exclusively resides, the Gram-negative bacterial pathogen Moraxella catarrhalis utilizes surface receptors for acquiring iron directly from human Tf and Lf. The receptors are comprised of a surface lipoprotein to capture iron-loaded Tf or Lf and deliver it to a TonB-dependent transporter (TBDT) for removal of iron and transport across the outer membrane. The subsequent transport of iron into the cell is normally mediated by a periplasmic iron-binding protein and inner membrane transport complex, which has yet to be determined for Moraxella catarrhalis. We identified two potential periplasm to cytoplasm transport systems and performed structural and functional studies with the periplasmic binding proteins (FbpA and AfeA) to evaluate their role. Growth studies with strains deleted in the fbpA or afeA gene demonstrated that FbpA, but not AfeA, was required for growth on human Tf or Lf. The crystal structure of FbpA with bound iron in the open conformation was obtained, identifying three tyrosine ligands that were required for growth on Tf or Lf. Computational modeling of the YfeA homologue, AfeA, revealed conserved residues involved in metal binding.
中文翻译:

革兰氏阴性细菌病原体中乳铁蛋白和转铁蛋白获取铁的结构和功能见解
铁是各种生命形式的必需元素,但由于元古代时期地球大气和海洋的氧化,铁在很大程度上是不可溶的。后生动物进化出铁转运糖蛋白,如转铁蛋白 (Tf) 和乳铁蛋白 (Lf),以保持铁处于无毒、可用的形式,同时维持体内较低的游离铁浓度,从而无法维持细菌生长。为了在其专门栖息的人类呼吸道粘膜表面生存,革兰氏阴性细菌病原体卡他莫拉氏菌利用表面受体直接从人类 Tf 和 Lf 获取铁。这些受体由表面脂蛋白组成,可捕获载铁的 Tf 或 Lf,并将其递送至 TonB 依赖性转运蛋白 (TBDT),以去除铁并转运穿过外膜。随后铁进入细胞的转运通常是由周质铁结合蛋白和内膜转运复合物介导的,对于卡他莫拉菌来说,这一点尚未确定。我们鉴定了两种潜在的周质到细胞质运输系统,并用周质结合蛋白(FbpA 和 AfeA)进行结构和功能研究,以评估它们的作用。使用fbpA或afeA中删除的菌株进行生长研究基因证明,在人 Tf 或 Lf 上生长需要 FbpA,而不是 AfeA。获得了开放构象中结合铁的 FbpA 的晶体结构,确定了在 Tf 或 Lf 上生长所需的三种酪氨酸配体。YfeA 同源物 AfeA 的计算模型揭示了参与金属结合的保守残基。