Copper binding leads to increased dynamics in the regulatory N-terminal domain of full-length human copper transporter ATP7B
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Copper binding leads to increased dynamics in the regulatory N-terminal domain of full-length human copper transporter ATP7B. / Orädd, Fredrik; Steffen, Jonas Hyld; Gourdon, Pontus; Andersson, Magnus.
I: PLOS Computational Biology, Bind 18, Nr. 9 September, e1010074, 2022.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - Copper binding leads to increased dynamics in the regulatory N-terminal domain of full-length human copper transporter ATP7B
AU - Orädd, Fredrik
AU - Steffen, Jonas Hyld
AU - Gourdon, Pontus
AU - Andersson, Magnus
N1 - Publisher Copyright: © 2022 Orädd et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2022
Y1 - 2022
N2 - ATP7B is a human copper-transporting P1B-type ATPase that is involved in copper homeostasis and resistance to platinum drugs in cancer cells. ATP7B consists of a copper-transporting core and a regulatory N-terminal tail that contains six metal-binding domains (MBD1-6) connected by linker regions. The MBDs can bind copper, which changes the dynamics of the regulatory domain and activates the protein, but the underlying mechanism remains unknown. To identify possible copper-specific structural dynamics involved in transport regulation, we constructed a model of ATP7B spanning the N-terminal tail and core catalytic domains and performed molecular dynamics (MD) simulations with (holo) and without (apo) copper ions bound to the MBDs. In the holo protein, MBD2, MBD3 and MBD5 showed enhanced mobilities, which resulted in a more extended N-terminal regulatory region. The observed separation of MBD2 and MBD3 from the core protein supports a mechanism where copper binding activates the ATP7B protein by reducing interactions among MBD1-3 and between MBD1-3 and the core protein. We also observed an increased interaction between MBD5 and the core protein that brought the copper-binding site of MBD5 closer to the high-affinity internal copper-binding site in the core protein. The simulation results assign specific, mechanistic roles to the metal-binding domains involved in ATP7B regulation that are testable in experimental settings.
AB - ATP7B is a human copper-transporting P1B-type ATPase that is involved in copper homeostasis and resistance to platinum drugs in cancer cells. ATP7B consists of a copper-transporting core and a regulatory N-terminal tail that contains six metal-binding domains (MBD1-6) connected by linker regions. The MBDs can bind copper, which changes the dynamics of the regulatory domain and activates the protein, but the underlying mechanism remains unknown. To identify possible copper-specific structural dynamics involved in transport regulation, we constructed a model of ATP7B spanning the N-terminal tail and core catalytic domains and performed molecular dynamics (MD) simulations with (holo) and without (apo) copper ions bound to the MBDs. In the holo protein, MBD2, MBD3 and MBD5 showed enhanced mobilities, which resulted in a more extended N-terminal regulatory region. The observed separation of MBD2 and MBD3 from the core protein supports a mechanism where copper binding activates the ATP7B protein by reducing interactions among MBD1-3 and between MBD1-3 and the core protein. We also observed an increased interaction between MBD5 and the core protein that brought the copper-binding site of MBD5 closer to the high-affinity internal copper-binding site in the core protein. The simulation results assign specific, mechanistic roles to the metal-binding domains involved in ATP7B regulation that are testable in experimental settings.
UR - http://www.scopus.com/inward/record.url?scp=85138184254&partnerID=8YFLogxK
U2 - 10.1371/journal.pcbi.1010074
DO - 10.1371/journal.pcbi.1010074
M3 - Journal article
C2 - 36070320
AN - SCOPUS:85138184254
VL - 18
JO - P L o S Computational Biology (Online)
JF - P L o S Computational Biology (Online)
SN - 1553-734X
IS - 9 September
M1 - e1010074
ER -
ID: 321168435