Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

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 LU and Andersson, Magnus (2022) In PLoS Computational Biology 18(9 September).
Abstract

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... (More)

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.

(Less)
Please use this url to cite or link to this publication:
author
; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
PLoS Computational Biology
volume
18
issue
9 September
article number
e1010074
publisher
Public Library of Science (PLoS)
external identifiers
  • scopus:85138184254
  • pmid:36070320
ISSN
1553-734X
DOI
10.1371/journal.pcbi.1010074
language
English
LU publication?
yes
id
7fd499a0-1cca-45d5-9c94-a8210b7007f5
date added to LUP
2022-12-02 10:46:49
date last changed
2025-04-18 20:02:54
@article{7fd499a0-1cca-45d5-9c94-a8210b7007f5,
  abstract     = {{<p>ATP7B is a human copper-transporting P<sub>1B</sub>-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.</p>}},
  author       = {{Orädd, Fredrik and Steffen, Jonas Hyld and Gourdon, Pontus and Andersson, Magnus}},
  issn         = {{1553-734X}},
  language     = {{eng}},
  month        = {{09}},
  number       = {{9 September}},
  publisher    = {{Public Library of Science (PLoS)}},
  series       = {{PLoS Computational Biology}},
  title        = {{Copper binding leads to increased dynamics in the regulatory N-terminal domain of full-length human copper transporter ATP7B}},
  url          = {{http://dx.doi.org/10.1371/journal.pcbi.1010074}},
  doi          = {{10.1371/journal.pcbi.1010074}},
  volume       = {{18}},
  year         = {{2022}},
}