Copper-transporting P-type ATPases use a unique ion-release pathway

TY - JOUR

T1 - Copper-transporting P-type ATPases use a unique ion-release pathway

AU - Andersson, Magnus

AU - Mattle, Daniel

AU - Sitsel, Oleg

AU - Klymchuk, Tetyana

AU - Nielsen, Anna Marie

AU - Møller, Lisbeth Birk

AU - White, Stephen H

AU - Nissen, Poul

AU - Gourdon, Pontus

PY - 2014

Y1 - 2014

N2 - Heavy metals in cells are typically regulated by PIB-type ATPases. The first structure of the class, a Cu(+)-ATPase from Legionella pneumophila (LpCopA), outlined a copper transport pathway across the membrane, which was inferred to be occluded. Here we show by molecular dynamics simulations that extracellular water solvated the transmembrane (TM) domain, results indicative of a Cu(+)-release pathway. Furthermore, a new LpCopA crystal structure determined at 2.8-Å resolution, trapped in the preceding E2P state, delineated the same passage, and site-directed-mutagenesis activity assays support a functional role for the conduit. The structural similarities between the TM domains of the two conformations suggest that Cu(+)-ATPases couple dephosphorylation and ion extrusion differently than do the well-characterized PII-type ATPases. The ion pathway explains why certain Menkes' and Wilson's disease mutations impair protein function and points to a site for inhibitors targeting pathogens.

AB - Heavy metals in cells are typically regulated by PIB-type ATPases. The first structure of the class, a Cu(+)-ATPase from Legionella pneumophila (LpCopA), outlined a copper transport pathway across the membrane, which was inferred to be occluded. Here we show by molecular dynamics simulations that extracellular water solvated the transmembrane (TM) domain, results indicative of a Cu(+)-release pathway. Furthermore, a new LpCopA crystal structure determined at 2.8-Å resolution, trapped in the preceding E2P state, delineated the same passage, and site-directed-mutagenesis activity assays support a functional role for the conduit. The structural similarities between the TM domains of the two conformations suggest that Cu(+)-ATPases couple dephosphorylation and ion extrusion differently than do the well-characterized PII-type ATPases. The ion pathway explains why certain Menkes' and Wilson's disease mutations impair protein function and points to a site for inhibitors targeting pathogens.

U2 - 10.1038/nsmb.2721

DO - 10.1038/nsmb.2721

M3 - Journal article

C2 - 24317491

SN - 1545-9993

VL - 21

SP - 43

EP - 48

JO - Nature Structural and Molecular Biology

JF - Nature Structural and Molecular Biology

ER -