TY - JOUR
T1 - Cα-trace model of the transmembrane domain of human copper transporter 1, motion and functional implications
AU - Schushan, Maya
AU - Barkan, Yariv
AU - Haliloglu, Turkan
AU - Ben-Tal, Nir
PY - 2010/6/15
Y1 - 2010/6/15
N2 - The trimeric human copper transporter 1 (hCTR1) is essential for copper uptake and is implicated in sensitivity to chemotherapy drugs. Using the cryoelectron microscopy (cryoEM) map of hCTR1 and evolutionary data, we constructed a Cα-trace model of the membrane region. The model structure, supported by mutagenesis data, was used to investigate global dynamics through elastic network models. Identified as dominant hinge regions, hCTR1's MxxxM and GxxxG motifs were shown to have significant roles in functional movements characterized by the two slowest modes of motion. Both modes predicted significant changes at the wide cytoplasmic pore region; the slowest mode introduced a rotational motion around the pore central axis, whereas in the following mode the cytoplasmic parts of the helices approached and moved away from the pore center. In the most cooperative mode, the MxxxM motif in the extracellular narrow region remained static. The second mode of motion, however, predicted a cooperative rotational motion of this copper-binding motif, possibly reflecting activation at the pore's extracellular entrance. We suggest a molecular mechanism of copper transport in which this motif serves both as a gate and as a selectivity filter. We also suggest residues that are responsible for pH activation.
AB - The trimeric human copper transporter 1 (hCTR1) is essential for copper uptake and is implicated in sensitivity to chemotherapy drugs. Using the cryoelectron microscopy (cryoEM) map of hCTR1 and evolutionary data, we constructed a Cα-trace model of the membrane region. The model structure, supported by mutagenesis data, was used to investigate global dynamics through elastic network models. Identified as dominant hinge regions, hCTR1's MxxxM and GxxxG motifs were shown to have significant roles in functional movements characterized by the two slowest modes of motion. Both modes predicted significant changes at the wide cytoplasmic pore region; the slowest mode introduced a rotational motion around the pore central axis, whereas in the following mode the cytoplasmic parts of the helices approached and moved away from the pore center. In the most cooperative mode, the MxxxM motif in the extracellular narrow region remained static. The second mode of motion, however, predicted a cooperative rotational motion of this copper-binding motif, possibly reflecting activation at the pore's extracellular entrance. We suggest a molecular mechanism of copper transport in which this motif serves both as a gate and as a selectivity filter. We also suggest residues that are responsible for pH activation.
KW - Dynamics
KW - Mechanism
KW - Model structure
KW - Structural bioinformatics
KW - hCTR1
UR - http://www.scopus.com/inward/record.url?scp=77954629362&partnerID=8YFLogxK
U2 - 10.1073/pnas.0914717107
DO - 10.1073/pnas.0914717107
M3 - מאמר
C2 - 20534491
AN - SCOPUS:77954629362
VL - 107
SP - 10908
EP - 10913
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 24
ER -