Busenlehner Laura S, Pennella Mario A, Giedroc David P
Department of Biochemistry and Biophysics, Center for Advanced Biomolecular Research, 2128 TAMU, Texas A&M University, College Station, TX 77843-2128, USA.
FEMS Microbiol Rev. 2003 Jun;27(2-3):131-43. doi: 10.1016/S0168-6445(03)00054-8.
The SmtB/ArsR family of prokaryotic metalloregulatory transcriptional repressors represses the expression of operons linked to stress-inducing concentrations of di- and multivalent heavy metal ions. Derepression results from direct binding of metal ions by these homodimeric "metal sensor" proteins. An evolutionary analysis, coupled with comparative structural and spectroscopic studies of six SmtB/ArsR family members, suggests a unifying "theme and variations" model, in which individual members have evolved distinct metal selectivity profiles by alteration of one or both of two structurally distinct metal coordination sites. These two metal sites are designated alpha3N (or alpha3) and alpha5 (or alpha5C), named for the location of the metal binding ligands within the known or predicted secondary structure of individual family members. The alpha3N/alpha3 sensors, represented by Staphylococcus aureus pI258 CadC, Listeria monocytogenes CadC and Escherichia coli ArsR, form cysteine thiolate-rich coordination complexes (S(3) or S(4)) with thiophilic heavy metal pollutants including Cd(II), Pb(II), Bi(III) and As(III) via inter-subunit coordination by ligands derived from the alpha3 helix and the N-terminal "arm" (CadCs) or from the alpha3 helix only (ArsRs). The alpha5/alpha5C sensors Synechococcus SmtB, Synechocystis ZiaR, S. aureus CzrA, and Mycobacterium tuberculosis NmtR form metal complexes with biologically required metal ions Zn(II), Co(II) and Ni(II) characterized by four or more coordination bonds to a mixture of histidine and carboxylate ligands derived from the C-terminal alpha5 helices on opposite subunits. Direct binding of metal ions to either the alpha3N or alpha5 sites leads to strong, negative allosteric regulation of repressor operator/promoter binding affinity, consistent with a simple model for derepression. We hypothesize that distinct allosteric pathways for metal sensing have co-evolved with metal specificities of distinct alpha3N and alpha5 coordination complexes.
原核生物金属调节转录阻遏物的SmtB/ArsR家族可抑制与二价和多价重金属离子应激诱导浓度相关的操纵子的表达。去阻遏是由这些同二聚体“金属传感器”蛋白直接结合金属离子导致的。一项进化分析，结合对六个SmtB/ArsR家族成员的比较结构和光谱研究，提出了一个统一的“主题与变体”模型，其中各个成员通过改变两个结构不同的金属配位位点中的一个或两个，进化出了不同的金属选择性谱。这两个金属位点被命名为α3N（或α3）和α5（或α5C），是以金属结合配体在各个家族成员已知或预测的二级结构中的位置命名的。α3N/α3传感器，以金黄色葡萄球菌pI258 CadC、单核细胞增生李斯特菌CadC和大肠杆菌ArsR为代表，通过源自α3螺旋和N端“臂”（CadCs）或仅源自α3螺旋（ArsRs）的配体进行亚基间配位，与包括Cd(II)、Pb(II)、Bi(III)和As(III)在内的亲硫重金属污染物形成富含半胱氨酸硫醇盐的配位络合物（S(3)或S(4)）。α5/α5C传感器集胞藻SmtB、集胞藻ZiaR、金黄色葡萄球菌CzrA和结核分枝杆菌NmtR与生物必需的金属离子Zn(II)、Co(II)和Ni(II)形成金属络合物，其特征是与来自相对亚基C端α5螺旋的组氨酸和羧酸盐配体混合物形成四个或更多配位键。金属离子直接结合到α3N或α5位点会导致阻遏物操纵子/启动子结合亲和力的强烈负变构调节，这与去阻遏的简单模型一致。我们假设，不同的金属传感变构途径与不同的α3N和α5配位络合物的金属特异性共同进化。
