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

Pujol Gimenez, Jonai; Hediger, Matthias; Gyimesi, Gergely (2017). A novel proton transfer mechanism in the SLC11 family of divalent metal ion transporters. Scientific Reports, 7(1), p. 6194. Nature Publishing Group 10.1038/s41598-017-06446-y

[img]
Preview
Text
41598_2017_Article_6446.pdf - Published Version
Available under License Creative Commons: Attribution (CC-BY).

Download (5MB) | Preview

In humans, the H(+)-coupled Fe(2+) 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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine

UniBE Contributor:

Pujol Gimenez, Jonai; Hediger, Matthias and Gyimesi, Gergely

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

2045-2322

Publisher:

Nature Publishing Group

Language:

English

Submitter:

Kevin Marc Rupp

Date Deposited:

20 Nov 2017 16:34

Last Modified:

26 Nov 2017 02:19

Publisher DOI:

10.1038/s41598-017-06446-y

PubMed ID:

28754960

BORIS DOI:

10.7892/boris.106119

URI:

https://boris.unibe.ch/id/eprint/106119

Actions (login required)

Edit item Edit item
Provide Feedback