TY - JOUR
T1 - Juggling cadmium detoxification and zinc homeostasis
T2 - A division of labour between the two C. elegans metallothioneins
AU - Essig, Yona J.
AU - Leszczyszyn, Oksana I.
AU - Almutairi, Norah
AU - Harrison-Smith, Alexandra
AU - Blease, Alix
AU - Zeitoun-Ghandour, Sukaina
AU - Webb, Sam M.
AU - Blindauer, Claudia A.
AU - Stürzenbaum, Stephen R.
N1 - Publisher Copyright:
© 2023 The Authors
PY - 2024/2
Y1 - 2024/2
N2 - The chemical properties of toxic cadmium and essential zinc are very similar, and organisms require intricate mechanisms that drive selective handling of metals. Previously regarded as unspecific “metal sponges”, metallothioneins (MTLs) are emerging as metal selectivity filters. By utilizing C. elegans mtl-1 and mtl-2 knockout strains, metal accumulation in single worms, single copy fluorescent-tagged transgenes, isoform specific qPCR and lifespan studies it was possible to demonstrate that the handling of cadmium and zinc by the two C. elegans metallothioneins differs fundamentally: the MTL-2 protein can handle both zinc and cadmium, but when it becomes unavailable, either via a knockout or by elevated cadmium exposure, MTL-1 takes over zinc handling, leaving MTL-2 to sequester cadmium. This division of labour is reflected in the folding behaviour of the proteins: MTL-1 folded well in presence of zinc but not cadmium, the reverse was the case for MTL-2. These differences are in part mediated by a zinc-specific mononuclear His3Cys site in the C-terminal insertion of MTL-1; its removal affected the entire C-terminal domain and may shift its metal selectivity towards zinc. Overall, we uncover how metallothionein isoform-specific responses and protein properties allow C. elegans to differentiate between toxic cadmium and essential zinc.
AB - The chemical properties of toxic cadmium and essential zinc are very similar, and organisms require intricate mechanisms that drive selective handling of metals. Previously regarded as unspecific “metal sponges”, metallothioneins (MTLs) are emerging as metal selectivity filters. By utilizing C. elegans mtl-1 and mtl-2 knockout strains, metal accumulation in single worms, single copy fluorescent-tagged transgenes, isoform specific qPCR and lifespan studies it was possible to demonstrate that the handling of cadmium and zinc by the two C. elegans metallothioneins differs fundamentally: the MTL-2 protein can handle both zinc and cadmium, but when it becomes unavailable, either via a knockout or by elevated cadmium exposure, MTL-1 takes over zinc handling, leaving MTL-2 to sequester cadmium. This division of labour is reflected in the folding behaviour of the proteins: MTL-1 folded well in presence of zinc but not cadmium, the reverse was the case for MTL-2. These differences are in part mediated by a zinc-specific mononuclear His3Cys site in the C-terminal insertion of MTL-1; its removal affected the entire C-terminal domain and may shift its metal selectivity towards zinc. Overall, we uncover how metallothionein isoform-specific responses and protein properties allow C. elegans to differentiate between toxic cadmium and essential zinc.
KW - Cadmium
KW - Caenorhabditis elegans
KW - Detoxification
KW - Metallothionein
UR - http://www.scopus.com/inward/record.url?scp=85181767534&partnerID=8YFLogxK
U2 - 10.1016/j.chemosphere.2023.141021
DO - 10.1016/j.chemosphere.2023.141021
M3 - Article
C2 - 38151062
AN - SCOPUS:85181767534
SN - 0045-6535
VL - 350
JO - Chemosphere
JF - Chemosphere
M1 - 141021
ER -