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).
Highlights
The myelin sheath plays a crucial role in increasing the speed of action potentials along neuronal axons in the vertebrate nervous system
The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies
Based on secondary structure predictions [65,66], N-myc downstream-regulated gene 1 (NDRG1) is composed of a short N-terminal region, a central a/b hydrolase domain including a cap region and a flexible C-terminal region consisting of three 10-amino acid (GTRSRSHTSE) tandem repeats not found in other NDRG family members (Fig. 1)
Summary
The myelin sheath plays a crucial role in increasing the speed of action potentials along neuronal axons in the vertebrate nervous system. Myelin is produced by oligodendrocytes in the central nervous system (CNS) and Schwann cells in the peripheral nervous system (PNS). The importance of the insulative nature of myelin is highlighted by severe neurological defects caused by myelin loss (demyelination) as a consequence of disease, such as multiple sclerosis, GuillainBarre syndrome or Charcot-Marie-Tooth disease (CMT). Charcot-Marie-Tooth disease is the most common hereditary demyelinating neuropathy affecting peripheral nerves, and it can be divided into subtypes based on electrodiagnostic findings and inheritance patterns [2,3]. The founding mutation R148X affects CNS myelin [13,14]. A neuropathy with similar symptoms caused by mutations in NDRG1 has been observed in certain dog breeds, such as Greyhounds [15] and Alaskan Malamutes [16]
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