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The two-domain elevator-type mechanism of zinc-transporting ZIP proteins

Wiuf, Anders ; Steffen, Jonas Hyld ; Becares, Eva Ramos ; Grønberg, Christina ; Mahato, Dhani Ram ; Rasmussen, Søren G.F. ; Andersson, Magnus ; Croll, Tristan ; Gotfryd, Kamil and Gourdon, Pontus LU (2022) In Science Advances 8(28).
Abstract

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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Science Advances
volume
8
issue
28
article number
eabn4331
publisher
American Association for the Advancement of Science (AAAS)
external identifiers
  • scopus:85134645174
  • pmid:35857505
ISSN
2375-2548
DOI
10.1126/sciadv.abn4331
language
English
LU publication?
yes
id
fb119da9-d83e-4de2-9aa8-713d984a6070
date added to LUP
2022-09-28 10:59:46
date last changed
2024-06-27 21:02:03
@article{fb119da9-d83e-4de2-9aa8-713d984a6070,
  abstract     = {{<p>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.</p>}},
  author       = {{Wiuf, Anders and Steffen, Jonas Hyld and Becares, Eva Ramos and Grønberg, Christina and Mahato, Dhani Ram and Rasmussen, Søren G.F. and Andersson, Magnus and Croll, Tristan and Gotfryd, Kamil and Gourdon, Pontus}},
  issn         = {{2375-2548}},
  language     = {{eng}},
  number       = {{28}},
  publisher    = {{American Association for the Advancement of Science (AAAS)}},
  series       = {{Science Advances}},
  title        = {{The two-domain elevator-type mechanism of zinc-transporting ZIP proteins}},
  url          = {{http://dx.doi.org/10.1126/sciadv.abn4331}},
  doi          = {{10.1126/sciadv.abn4331}},
  volume       = {{8}},
  year         = {{2022}},
}