Journal
BIOCHEMISTRY
Volume 58, Issue 45, Pages 4570-4581Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.biochem.9b00830
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Funding
- Austrian Science Fund
- Swiss National Science Foundation (Dach Project) [I 1482-N28]
- Spanish Ministerio de Ciencia e Innovacion
- FEDER [BIO2015-67358-C2-2-P]
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Metallothioneins (MTs) are cysteine-rich polypeptides that are naturally found coordinated to monovalent and/or divalent transition metal ions. Three metallothionein isoforms from the Roman snail Helix pomatia are known. They differ in their physiological metal load and in their specificity for transition metal ions such as Cd2+ (HpCdMT isoform) and Cu+ (HpCuMT isoform) or in the absence of a defined metal specificity (HpCd/CuMT isoform). We have determined the solution structure of the Cd-specific isoform (HpCdMT) by nuclear magnetic resonance spectroscopy using recombinant isotopically labeled protein loaded with Zn2+ or Cd2+. Both structures display two-domain architectures, where each domain comprises a characteristic three-metal cluster similar to that observed in the beta-domains of vertebrate MTs. The polypeptide backbone is well-structured over the entire sequence, including the interdomain linker. Interestingly, the two domains display mutual contacts, as observed before for the metallothionein of the snail Littorina littorea, to which both N- and C-terminal domains are highly similar. Increasing the length of the linker motionally decouples both domains and removes mutual contacts between them without having a strong effect on the stability of the individual domains. The structures of Cd-6- and Zn-6-HpCdMT are nearly identical. However, N-15 relaxation, in particular N-15 R-2 rates, is accelerated for many residues of Zn-6-HpCdMT but not for Cd-6-HpCdMT, revealing the presence of conformational exchange effects. We suggest that this snail MT isoform is evolutionarily optimized for binding Cd rather than Zn.
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