Computation and Functional Studies Provide a Model for the Structure of the Zinc Transporter hZIP4*

By Sagar Antala, Sergey Ovchinnikov, Hetunandan Kamisetty, David Baker, R. Dempski. 2015

64 citations recorded by the source corpus.

Background: ZIP transporters increase the cytosolic concentration of first row transition metals. Results: We have developed a structural model of hZIP4 by combining protein prediction methods with in situ experiments. Conclusion: Analysis of our experiments provides insight into the permeation pathway of hZIP4. Significance: Comparison of this model to membrane transporter crystal structures provides a structural linkage to MFS proteins. Members of the Zrt and Irt protein (ZIP) family are a central participant in transition metal homeostasis as they function to increase the cytosolic concentration of zinc and/or iron. However, the lack of a crystal structure hinders elucidation of the molecular mechanism of ZIP proteins. Here, we employed GREMLIN, a co-evolution-based contact prediction approach in conjunction with the Rosetta structure prediction program to construct a structural model of the human (h) ZIP4 transporter. The predicted contact data are best fit by modeling hZIP4 as a dimer. Mutagenesis of residues that comprise a central putative hZIP4 transmembrane transition metal coordination site in the structural model alter the kinetics and specificity of hZIP4. Comparison of the hZIP4 dimer model to all known membrane protein structures identifies the 12-transmembrane monomeric Piriformospora indica phosphate transporter (PiPT), a member of the major facilitator superfamily (MFS), as a likely structural homolog.

Subfields: Health, Toxicology and Mutagenesis, Hematology, Nutrition and Dietetics

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In Nutrition and Dietetics

Citations in the corpus

Large-scale determination of previously unsolved protein structures using evolutionary information (2015, methodology): “…from such predictions have been used to model a wide range of unknown protein structures ( Hayat et al., 2014 ; Wickles et al., 2014 ; Abriata, 2015 ; Antala et al., 2015 ; Hopf et al., 2015 ; Tian et al., 2015 ) and protein–protein complexes ( Ovchinnikov et al., 2014 ; Hopf et al., 2014 ).”
Applications of sequence coevolution in membrane protein biochemistry (2017, unknown): “This approach has been applied to the human zincregulated transporter protein hZIP4, where Rosetta and evolutionary constraints helped build a dimeric model of the transporter [121].”
A computational study of the structure and function of human Zrt and Irt-like proteins metal transporters: An elevator-type transport mechanism predicted by AlphaFold2 (2022, background): “Indeed, a key role for these residues is supported by experimental data (Antala et al., 2015; see also https://www.ncbi.nlm.nih.gov/clinvar/ RCV000348067/).”