1. Structural insights into Charcot–Marie–Tooth disease‐linked mutations in human GDAP1
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Aleksi Sutinen, Giang Thi Tuyet Nguyen, Arne Raasakka, Gopinath Muruganandam, Remy Loris, Emil Ylikallio, Henna Tyynismaa, Luca Bartesaghi, Salla Ruskamo, Petri Kursula, STEMM - Stem Cells and Metabolism Research Program, HUS Neurocenter, University of Helsinki, Neurologian yksikkö, Centre of Excellence in Stem Cell Metabolism, Department of Medical and Clinical Genetics, Research Programs Unit, Henna Tyynismaa / Principal Investigator, Structural Biology Brussels, Department of Bio-engineering Sciences, and Faculty of Sciences and Bioengineering Sciences
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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 - Abstract
FEBS Open Bio 12(7), 1306 - 1324 (2022). doi:10.1002/2211-5463.13422, 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., Published by Wiley, Hoboken, NJ
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- 2022
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