Crystal and solution structure of NDRG1, a membrane-binding protein linked to myelination and tumour suppression

Venla Mustonen, Gopinath Muruganandam, Remy Loris, Petri Kursula, Salla Ruskamo

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10 Citaten (Scopus)
144 Downloads (Pure)

Samenvatting

N‐myc downstream‐regulated gene 1 (NDRG1) is a tumour suppressor involved in vesicular trafficking and stress response. NDRG1 participates in peripheral nerve myelination, and mutations in the NDRG1 gene lead to Charcot‐Marie‐Tooth neuropathy. The 43‐kDa NDRG1 is considered as an inactive member of the α/β hydrolase superfamily. In addition to a central α/β hydrolase fold domain, NDRG1 consists of a short N terminus and a C‐terminal region with three 10‐residue repeats. We determined the crystal structure of the α/β hydrolase domain of human NDRG1 and characterised the structure and dynamics of full‐length NDRG1. The structure of the α/β hydrolase domain resembles the canonical α/β hydrolase fold with a central β sheet surrounded by α helices. Small‐angle X‐ray scattering and CD spectroscopy indicated a variable conformation for the N‐ and C‐terminal regions. NDRG1 binds to various types of lipid vesicles, and the conformation of the C‐terminal region is modulated upon lipid interaction. Intriguingly, NDRG1 interacts with metal ions, such as nickel, but is prone to aggregation in their presence. Our results uncover the structural and dynamic features of NDRG1, as well as elucidate its interactions with metals and lipids, and encourage studies to identify a putative hydrolase activity of NDRG1.
Originele taal-2English
Pagina's (van-tot)3507-3529
Aantal pagina's23
TijdschriftThe FEBS Journal
Volume288
Nummer van het tijdschrift11
DOI's
StatusPublished - 7 jun 2021

Bibliografische nota

Funding Information:
This work was funded by Jane and Aatos Erkko Foundation and the Academy of Finland, grant number 315272. The research leading to this result has been supported by the project iNEXT, grant number 653706 and CALIPSOplus, grant number 730872, from the EU Framework Programme for Research and Innovation HORIZON 2020. We acknowledge DESY (Hamburg, Germany), a member of the Helmholtz Association HGF, for the provision of experimental facilities. Parts of this research were carried out at PETRA III, and we would like to thank P11 beamline personnel. We acknowledge the instrumentation and personnel at Diamond Light Source, instrument B21, at SOLEIL beamline SWING and at ISA, AU-CD. The use of the facilities and expertise of the Biocenter Oulu Proteomics and protein analysis and Structural Biology core facilities, members of Biocenter Finland, Instruct-ERIC Centre Finland and FINStruct, is gratefully acknowledged.

Funding Information:
This work was funded by Jane and Aatos Erkko Foundation and the Academy of Finland, grant number 315272. The research leading to this result has been supported by the project iNEXT, grant number 653706 and CALIPSOplus, grant number 730872, from the EU Framework Programme for Research and Innovation HORIZON 2020. We acknowledge DESY (Hamburg, Germany), a member of the Helmholtz Association HGF, for the provision of experimental facilities. Parts of this research were carried out at PETRA III, and we would like to thank P11 beamline personnel. We acknowledge the instrumentation and personnel at Diamond Light Source, instrument B21, at SOLEIL beamline SWING and at ISA, AU‐CD. The use of the facilities and expertise of the Biocenter Oulu Proteomics and protein analysis and Structural Biology core facilities, members of Biocenter Finland, Instruct‐ERIC Centre Finland and FINStruct, is gratefully acknowledged.

Publisher Copyright:
© 2020 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

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