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In vivo ‐folded metal–metallothionein 3 complexes reveal the Cu–thionein rather than Zn–thionein character of this brain‐specific mammalian metallothionein
Author(s) -
Artells Ester,
Palacios Òscar,
Capdevila Mercè,
Atrian Sílvia
Publication year - 2014
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.12731
Subject(s) - metallothionein , metal , peptide , cytoplasm , gene isoform , chemistry , biophysics , metalloprotein , in vitro , in vivo , copper , metal ions in aqueous solution , recombinant dna , biochemistry , zinc , crystallography , biology , organic chemistry , gene , microbiology and biotechnology
Metallothionein‐3 ( MT 3) is one of the four mammalian metallothioneins ( MT ), and is constitutively synthesized in the brain. MT 3 acts both intracellularly and extracellularly in this organ, performing functions related to neuronal growth and physiological metal (Zn and Cu) handling. It appears to be involved in the prevention of neurodegenerative disorders caused by insoluble Cu–peptide aggregates, as it triggers a Zn–Cu swap that may counteract the deleterious presence of copper in neural tissues. The literature data on MT 3 coordination come from studies either on apo‐ MT 3 reconstitution or the reaction of Zn– MT 3 with Cu 2+ , an ion that is hardly present inside cells. To ascertain the MT 3 metal‐binding features in a scenario closer to the reductive cell cytoplasm, a study of the recombinant Zn 2+ , Cd 2+ and Cu + complexes of MT 3, β MT 3, and α MT 3, as well as the in vitro Zn 2+ –Cd 2+ and Zn 2+ –Cu + replacement processes, is presented here. We conclude that MT 3 has a Cu–thionein character that is stronger than that of the MT 1 and MT 2 isoforms – also present in the mammalian brain – which is mainly contributed by its β domain. In contrast, the α domain retains a high capacity to bind Zn 2+ ions, and, consequently, the entire MT 3 peptide shows a peculiar dual ability to handle both metal ions. The nature of the formed Cu + – MT 3 complexes oscillates from heterometallic Cu 6 Zn 4 – MT 3 to homometallic Cu 10 – MT 3 major species, in a narrow Cu concentration range. Therefore, the entire MT 3 peptide shows a high capacity to bind Cu + , provided that this occurs in a nonoxidative milieux. This reflects a peculiar property of this MT isoform, which accurately senses different Cu contents in the environment in which it is synthesized.