title: pH-dependent coordination of Pb2+ to metallothionein2: structures and insight into lead detoxification.
abstract: Lead is a toxic heavy metal whose detoxification in organisms is mainly carried out by its coordination with some metalloproteins such as metallothioneins (MTs). Two Pb-MT complexes, named as Pb7-MT2(I) and Pb7-MT2(II), form under neutral and weakly acidic conditions, respectively. However, the structures of the two complexes, which are crucial for a better understanding of the detoxification mechanism of Pb-MTs, have not been clearly elucidated. In this Work, coordination of Pb(2+) with rabbit liver apo-MT2, as well as with the two individual domains (apo-αMT2 and apo-βMT2) at different pH, were studied by combined spectroscopic (UV-visible, circular dichroism, and NMR) and computational methods. The results showed that in Pb7-MT2(I) the Pb(2+) coordination is in the trigonal pyramidal Pb-S3 mode, whereas the Pb7-MT2(II) complex contains mixed trigonal pyramidal Pb-S3, distorted trigonal pyramidal Pb-S2O1, and distorted quadrilateral pyramidal Pb-S3O1 modes. The O-donor ligand in Pb7-MT2(II) was identified as the carboxyl groups of the aspartic acid residues at positions 2 and 56. Our studies also revealed that Pb7-MT2(II) has a greater acid tolerance and coordination stability than Pb7-MT2(I), thereby retaining the Pb(2+) coordination at acidic pH. The higher flexibility of Pb7-MT2(II) renders it more accessible to lysosomal proteolysis than Pb7-MT2(I). Similar spectral features were observed in the coordination of Pb(2+) by human apo-MT2, suggesting a commonality among mammalian MT2s in the Pb(2+) coordination chemistry.
authors.affiliation: College of Chemistry and Chemical Engineering, Central South University , Changsha 410083, People's Republic of China.
authors.forename: Yonghui
authors.initials: Y
authors.lastname: He
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Liu
authors.forename: Narek
authors.initials: N
authors.lastname: Darabedian
authors.forename: Yizeng
authors.initials: Y
authors.lastname: Liang
authors.forename: Deyin
authors.initials: D
authors.lastname: Wu
authors.forename: Juan
authors.initials: J
authors.lastname: Xiang
authors.forename: Feimeng
authors.initials: F
authors.lastname: Zhou
mesh_terms: D000818:Animals; D002942:Circular Dichroism; D006863:Hydrogen-Ion Concentration; D008658:Inactivation, Metabolic; D007854:Lead / Q000737:chemistry* / Q000493:pharmacokinetics; D009682:Magnetic Resonance Spectroscopy; D008668:Metallothionein / Q000737:chemistry*; D011487:Protein Conformation; D059748:Proteolysis; D011817:Rabbits; D013056:Spectrophotometry, Ultraviolet
chemical_list: D007854:Lead; D008668:Metallothionein