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

Area of Science:

• Biochemistry
• Structural Biology
• Molecular Biology

Background:

• The Zrt and Irt protein (ZIP) family regulates transition metal homeostasis by controlling intracellular zinc and iron levels.
• Elucidating the molecular mechanisms of ZIP proteins is challenging due to the absence of their crystal structures.

Purpose of the Study:

• To construct a structural model of the human ZIP4 (hZIP4) transporter.
• To investigate the oligomeric state and functional residues of hZIP4.

Main Methods:

• Utilized GREMLIN, a co-evolution-based contact prediction method.
• Employed Rosetta structure prediction software for model building.
• Performed site-directed mutagenesis to assess residue function.

Main Results:

• The structural model suggests hZIP4 functions as a dimer.
• Mutagenesis of predicted metal coordination residues impacted hZIP4 kinetics and specificity.
• The hZIP4 dimer model shares structural homology with the Piriformospora indica phosphate transporter (PiPT).

Conclusions:

• The dimeric structure of hZIP4 is crucial for its function in transition metal transport.
• This study provides a structural basis for understanding hZIP4's role in zinc and iron homeostasis.
• hZIP4 may belong to the major facilitator superfamily (MFS) based on structural comparisons.