TY - JOUR

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 -