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Structural insights into Charcot–Marie–Tooth disease‐linked mutations in human GDAP1
- Source :
- FEBS Open Bio 12(7), 1306-1324 (2022). doi:10.1002/2211-5463.13422, FEBS Open Bio
- Publication Year :
- 2022
- Publisher :
- Deutsches Elektronen-Synchrotron, DESY, Hamburg, 2022.
-
Abstract
- FEBS Open Bio 12(7), 1306 - 1324 (2022). doi:10.1002/2211-5463.13422<br />Charcot–Marie–Tooth disease (CMT) is the most common inherited peripheral polyneuropathy in humans, and its different subtypes are linked to mutations in dozens of different genes. Mutations in ganglioside-induced differentiation-associated protein 1 (GDAP1) cause two types of CMT, demyelinating CMT4A and axonal CMT2K. The GDAP1-linked CMT genotypes are mainly missense point mutations. Despite clinical profiling and in vivo studies on the mutations, the etiology of GDAP1-linked CMT is poorly understood. Here, we describe the biochemical and structural properties of the Finnish founding CMT2K mutation H123R and CMT2K-linked R120W, both of which are autosomal dominant mutations. The disease variant proteins retain close to normal structure and solution behavior, but both present a significant decrease in thermal stability. Using GDAP1 variant crystal structures, we identify a side-chain interaction network between helices ⍺3, ⍺6, and ⍺7, which is affected by CMT mutations, as well as a hinge in the long helix ⍺6, which is linked to structural flexibility. Structural analysis of GDAP1 indicates that CMT may arise from disruption of specific intra- and intermolecular interaction networks, leading to alterations in GDAP1 structure and stability, and, eventually, insufficient motor and sensory neuron function.<br />Published by Wiley, Hoboken, NJ
- Subjects :
- EXPRESSION
congenital, hereditary, and neonatal diseases and abnormalities
Nerve Tissue Proteins
GDAP1
Charcot–Marie–Tooth disease
CLASSIFICATION
General Biochemistry, Genetics and Molecular Biology
protein-protein interaction
GLUTATHIONE-S-TRANSFERASE
Charcot-Marie-Tooth Disease
ddc:570
structural biology
SCATTERING
Humans
protein structure
X-ray crystallography
DIFFERENTIATION-ASSOCIATED PROTEIN-1
IDENTIFICATION
STABILITY
GST superfamily
3112 Neurosciences
stability
GENE
nervous system diseases
SINGLE
Mutation
neuropathy
3111 Biomedicine
GENERATION
Subjects
Details
- Language :
- English
- ISSN :
- 22115463
- Database :
- OpenAIRE
- Journal :
- FEBS Open Bio 12(7), 1306-1324 (2022). doi:10.1002/2211-5463.13422, FEBS Open Bio
- Accession number :
- edsair.doi.dedup.....858e5b8f341bfeb3f97cea7bb9fb94b8
- Full Text :
- https://doi.org/10.3204/pubdb-2022-02941