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Copper binding leads to increased dynamics in the regulatory N-terminal domain of full-length human copper transporter ATP7B
Open accessPreprint — published as 10.1371/journal.pcbi.1010074
Abstract
ATP7B is a human copper-transporting P 1B -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. Instead, an increased interaction between MBD5 and the core protein was observed 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.
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Highly accurate protein structure prediction with AlphaFold
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Metadata
- Authors
- Orädd, F., Steffen, J. H., Gourdon, P., & Andersson, M.
- Affiliations
- Umeå University (SE)
- University of Copenhagen (DK)
- Corresponding author
- Andersson, Magnus
- Venue
- PLoS Computational Biology
- Publisher
- openRxiv
- Published
- 2022-04-06
- Volume
- 18
- Issue
- 9
- Pages
- e1010074-e1010074
- ISSN
- 1553-734X (ISSN-L)
- PMC
- PMC9484656
- OpenAlex
- W4294884798
- Cited by
- 12
- References
- 1
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 3 · 2023: 1 · 2022: 1
- FWCI
- 0.65
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- PLoS Computational Biology (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
- DiVA at Umeå University (Umeå University) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- Crafoordska Stiftelsen (20200739, 20180652 & 20170818)
- Lundbeckfonden (20170818, R313-2019-774, 20200739, 20180652)
- Vetenskapsrådet (20180652, 2020-03840, R313-2019-774, 20200739, 20170818)
- H. Lundbeck A/S
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- ATP7B, copper transporters, metal-binding domain, copper binding, protein dynamics, N-terminal regulatory domain, copper homeostasis, P1B-type ATPase, protein activation mechanism, MBD5, platinum resistance
- MeSH terms
- Protein Domains, Copper-Transporting ATPases, Binding Sites, Copper, DNA-Binding Proteins, Humans
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