Crystal and solution structure of NDRG1, a membrane‐binding protein linked to myelination and tumour suppression. (22nd January 2021)

• Record Type: Journal Article
• Authors: Mustonen, Venla; Muruganandam, Gopinath; Loris, Remy; Kursula, Petri; Ruskamo, Salla
• Is Part Of: FEBS journal. Volume 288:Number 11(2021)
• Page Start: 3507
• Page End: 3529
• Publication Date: 2021-01-22
• Subjects: Charcot‐Marie‐Tooth disease -- crystal structure -- myelin -- small‐angle X‐ray scattering -- tumour suppressor gene; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; 572
• DOI: 10.1111/febs.15660
• Languages: English
• ISSNs: 1742-464X

Abstract

Abstract : 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. Databases: The coordinates and structure factors for the crystal structure of human NDRG1 were deposited to PDB (PDB ID: 6ZMM ). Abstract : N‐myc downstream‐regulated gene 1 (NDRG1) plays a role in the maintenance of the myelin sheaths in peripheral nerves. The crystal structure of the α/β hydrolase domain of human NDRG1 resembles the canonical α/β hydrolase fold. The N and C termini of NDRG1 are flexible and obtain variable conformations. NDRG1 binds to metal ions and lipid vesicles, and the conformation of the C‐terminal region is modulated upon lipid interaction.