Structural differences between Pb2+- and Ca2+-binding sites in proteins: Implications with respect to toxicity

Abstract

Pb2+ is known to displace physiologically-relevant metal ions in proteins. To investigate potential relationships between Pb2+/protein complexes and toxicity, data from the Protein Data Bank were analyzed to compare structural properties of Pb2+- and Ca2+-binding sites. Results of this analysis reveal that the majority of Pb2+ sites (77.1%) involve 2 to 5 binding ligands, compared with 6 ± 2 for non-EF-Hand and 7 ± 1 for EF-Hand Ca2+-binding sites. The mean net negative charge by site (1.7) fell between values noted for non-EF-Hand (1 ± 1) and EF-Hand (3 ± 1). Oxygen is the dominant ligand for both Pb2+ and Ca2+, but Pb2+ binds predominantly with sidechain Glu (38.4%), which is less prevalent in both non-EF-Hand (10.4%) and EF-Hand (26.6%) Ca2+-binding sites. A comparison of binding geometries where Pb2+ has replaced Ca2+ in calmodulin (CaM) and Zn2+ in 5-aminolaevulinic acid dehydratase (ALAD) revealed protein structural changes that appear to be unrelated to ionic displacement. Structural changes observed with CaM may be related to opportunistic binding of Pb2+ in regions of high electrostatic charge, whereas ALAD may bind multiple Pb2+ ions in the active site. These results suggest that Pb2+ adapts to structurally-diverse binding geometries and that opportunistic binding may play an active role in molecular metal toxicity.

Cd2+as a Ca2+Surrogate in Protein–Membrane Interactions: Isostructural but Not Isofunctional

“…21 Pb 2+ is a borderline Lewis acid that interacts readily with oxygen-containing ligands and can adopt CNs up to 9 in proteins. 22 …”

Interaction of Pb2+, PbMe22+ and PbPh22+ with 3-(phenyl)-2-sulfanylpropenoic acid: A coordinative and toxicological approach

“…This significant reduction could be due to the steric obstruction caused by the replacement of the Zn(II) ion present in the active site in the native enzyme by the PbMe 2þ 2 cation, one of the factors that is considered significant in the case of Pb 2+ intoxication [64]; however, as the partial metabolization of the organometallic cation to Pb 2+ cannot be ruled out, the electronic/ structural inactivation mechanism proposed for Pb 2+ could also be in operation in the present case [65,66].…”

Pb(II) Disruption of Synaptic Activity Through Ca(II)- and Zn(II)-binding Proteins

“…[60] . Consistent with these observations, evidence summarized recently in our lab and others increasingly indicates that Pb 2+ neurotoxicity is related to interference with synaptic activity [61,62] , which is likely associated with disruption of Zn 2+ and Ca 2+ -dependent functions by Pb 2+ [23,24] .…”

“…Indeed, studies have demonstrated that Pb 2+ can displace Mg 2+ in pyrimidine 5'-nucleotidase type 1 [71] , Fe 2+ in divalent cation transporter-1 [2] , Zn 2+ in 5-aminolevulinic acid dehydratase (ALAD) [72,73] , and Ca 2+ in a variety of Ca 2+ -binding proteins (CaBPs) [74][75][76][77][78] including PKC [79,80] , synaptotagmin [81] , and CaM [78,82] ; all proteins involved in neural pathways that represent targets for Pb 2+ -induced neurotoxicity. A comprehensive statistical analysis of Pb 2+ -bound structures in the Protein DataBank (PDB), revealed that Pb 2+ is remarkably adept at occupying the binding sites of physiologically relevant metal ions, despite differences in coordination numbers, coordination geometries, and ligand type [60] . Additionally, Pb 2+ was observed to bind in regions of proteins outside of previously identified primary metal binding sites, including potential auxiliary binding sites for Mg 2+ and Zn 2+ in CaM that may allosterically inhibit function of the protein [54] .…”