Journal
FEBS JOURNAL
Volume 288, Issue 11, Pages 3507-3529Publisher
WILEY
DOI: 10.1111/febs.15660
Keywords
Charcot-Marie-Tooth disease; crystal structure; myelin; small-angle X-ray scattering; tumour suppressor gene
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Funding
- Jane and Aatos Erkko Foundation
- Academy of Finland [315272]
- project iNEXT [653706]
- CALIPSOplus from the EU Framework Programme for Research and Innovation HORIZON 2020 [730872]
- Academy of Finland (AKA) [315272, 315272] Funding Source: Academy of Finland (AKA)
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NDRG1 is a tumor suppressor gene involved in peripheral nerve myelination with dynamic interaction with metals and lipids, potentially possessing hydrolase activity.
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 alpha/beta hydrolase superfamily. In addition to a central alpha/beta 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 alpha/beta hydrolase domain of human NDRG1 and characterised the structure and dynamics of full-length NDRG1. The structure of the alpha/beta hydrolase domain resembles the canonical alpha/beta hydrolase fold with a central beta sheet surrounded by alpha 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.
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