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Molecular mechanisms of Charcot-Marie-Tooth neuropathy linked to mutations in human myelin protein P2

DOI: 10.1038/s41598-017-06781-0 DOI Help

Authors: Salla Ruskamo (University of Oulu) , Tuomo Nieminen (Tampere University of Technology) , Cecilie K. Kristiansen (University of Bergen) , Guro H. Vatne (University of Bergen) , Anne Baumann (University of Bergen) , Erik I. Hallin (University of Bergen) , Arne Raasakka (University of Bergen) , Päivi Joensuu (University of Oulu) , Ulrich Bergmann (University of Oulu) , Ilpo Vattulainen (Tampere University of Technology; University of Helsinki) , Petri Kursula (University of Bergen)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Scientific Reports , VOL 7

State: Published (Approved)
Published: July 2017
Diamond Proposal Number(s): 14794

Open Access Open Access

Abstract: Charcot-Marie-Tooth (CMT) disease is one of the most common inherited neuropathies. Recently, three CMT1-associated point mutations (I43N, T51P, and I52T) were discovered in the abundant peripheral myelin protein P2. These mutations trigger abnormal myelin structure, leading to reduced nerve conduction velocity, muscle weakness, and distal limb atrophy. P2 is a myelin-specific protein expressed by Schwann cells that binds to fatty acids and membranes, contributing to peripheral myelin lipid homeostasis. We studied the molecular basis of the P2 patient mutations. None of the CMT1-associated mutations alter the overall folding of P2 in the crystal state. P2 disease variants show increased aggregation tendency and remarkably reduced stability, T51P being most severe. In addition, P2 disease mutations affect protein dynamics. Both fatty acid binding by P2 and the kinetics of its membrane interactions are affected by the mutations. Experiments and simulations suggest opening of the β barrel in T51P, possibly representing a general mechanism in fatty acid-binding proteins. Our findings demonstrate that altered biophysical properties and functional dynamics of P2 may cause myelin defects in CMT1 patients. At the molecular level, a few malformed hydrogen bonds lead to structural instability and misregulation of conformational changes related to ligand exchange and membrane binding.

Journal Keywords: Demyelinating diseases; Molecular biophysics; Structural biology

Diamond Keywords: Charcot‐Marie‐Tooth Disease (CMT)

Subject Areas: Biology and Bio-materials

Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Other Facilities: DESY; SOLEIL; ANKA

Added On: 09/08/2017 10:32


Discipline Tags:

Health & Wellbeing Neurology Structural biology Biophysics Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)