The two-domain elevator-type mechanism of zinc-transporting ZIP proteins
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The two-domain elevator-type mechanism of zinc-transporting ZIP proteins. / Wiuf, Anders; Steffen, Jonas Hyld; Becares, Eva Ramos; Gronberg, Christina; Mahato, Dhani Ram; Rasmussen, Soren G. F.; Andersson, Magnus; Croll, Tristan; Gotfryd, Kamil; Gourdon, Pontus.
I: Science Advances, Bind 8, Nr. 28, 4331, 2022.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - The two-domain elevator-type mechanism of zinc-transporting ZIP proteins
AU - Wiuf, Anders
AU - Steffen, Jonas Hyld
AU - Becares, Eva Ramos
AU - Gronberg, Christina
AU - Mahato, Dhani Ram
AU - Rasmussen, Soren G. F.
AU - Andersson, Magnus
AU - Croll, Tristan
AU - Gotfryd, Kamil
AU - Gourdon, Pontus
PY - 2022
Y1 - 2022
N2 - Zinc is essential for all organisms and yet detrimental at elevated levels. Hence, homeostasis of this metal is tightly regulated. The Zrt/Irt-like proteins (ZIPs) represent the only zinc importers in metazoans. Mutations in human ZIPs cause serious disorders, but the mechanism by which ZIPs transfer zinc remains elusive. Hitherto, structural information is only available for a model member, BbZIP, and as a single, ion-bound conformation, precluding mechanistic insights. Here, we elucidate an inward-open metal-free BbZIP structure, differing substantially in the relative positions of the two separate domains of ZIPs. With accompanying coevolutional analyses, mutagenesis, and uptake assays, the data point to an elevator-type transport mechanism, likely shared within the ZIP family, unifying earlier functional data. Moreover, the structure reveals a previously unknown ninth transmembrane segment that is important for activity in vivo. Our findings outline the mechanistic principles governing ZIP-protein transport and enhance the molecular understanding of ZIP-related disorders.
AB - Zinc is essential for all organisms and yet detrimental at elevated levels. Hence, homeostasis of this metal is tightly regulated. The Zrt/Irt-like proteins (ZIPs) represent the only zinc importers in metazoans. Mutations in human ZIPs cause serious disorders, but the mechanism by which ZIPs transfer zinc remains elusive. Hitherto, structural information is only available for a model member, BbZIP, and as a single, ion-bound conformation, precluding mechanistic insights. Here, we elucidate an inward-open metal-free BbZIP structure, differing substantially in the relative positions of the two separate domains of ZIPs. With accompanying coevolutional analyses, mutagenesis, and uptake assays, the data point to an elevator-type transport mechanism, likely shared within the ZIP family, unifying earlier functional data. Moreover, the structure reveals a previously unknown ninth transmembrane segment that is important for activity in vivo. Our findings outline the mechanistic principles governing ZIP-protein transport and enhance the molecular understanding of ZIP-related disorders.
KW - SYMPORTER
KW - MODEL
KW - IDENTIFICATION
KW - ENVIRONMENT
KW - INSIGHTS
KW - FAMILY
U2 - 10.1126/sciadv.abn4331
DO - 10.1126/sciadv.abn4331
M3 - Journal article
C2 - 35857505
VL - 8
JO - Science advances
JF - Science advances
SN - 2375-2548
IS - 28
M1 - 4331
ER -
ID: 314622440