Format

Send to

Choose Destination
Sci Rep. 2017 Jul 28;7(1):6194. doi: 10.1038/s41598-017-06446-y.

A novel proton transfer mechanism in the SLC11 family of divalent metal ion transporters.

Author information

1
Institute of Biochemistry and Molecular Medicine and National Center of Competence in Research, NCCR TransCure, University of Bern, Bern, Switzerland.
2
Institute of Biochemistry and Molecular Medicine and National Center of Competence in Research, NCCR TransCure, University of Bern, Bern, Switzerland. matthias.hediger@ibmm.unibe.ch.
3
Institute of Biochemistry and Molecular Medicine and National Center of Competence in Research, NCCR TransCure, University of Bern, Bern, Switzerland. gergely.gyimesi@ibmm.unibe.ch.

Abstract

In humans, the H+-coupled Fe2+ transporter DMT1 (SLC11A2) is essential for proper maintenance of iron homeostasis. While X-ray diffraction has recently unveiled the structure of the bacterial homologue ScaDMT as a LeuT-fold transporter, the exact mechanism of H+-cotransport has remained elusive. Here, we used a combination of molecular dynamics simulations, in silico pK a calculations and site-directed mutagenesis, followed by rigorous functional analysis, to discover two previously uncharacterized functionally relevant residues in hDMT1 that contribute to H+-coupling. E193 plays a central role in proton binding, thereby affecting transport properties and electrogenicity, while N472 likely coordinates the metal ion, securing an optimally "closed" state of the protein. Our molecular dynamics simulations provide insight into how H+-translocation through E193 is allosterically linked to intracellular gating, establishing a novel transport mechanism distinct from that of other H+-coupled transporters.

PMID:
28754960
PMCID:
PMC5533754
DOI:
10.1038/s41598-017-06446-y
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center