Structural insights into Charcot–Marie–Tooth disease-linked mutations in human GDAP1
Sutinen, Aleksi; Nguyen, Giang Thi Tuyet; Raasakka, Arne; Muruganandam, Gopinath; Loris, Remy; Ylikallio, Emil; Tyynismaa, Henna; Bartesaghi, Luca; Ruskamo, Salla; Kursula, Petri
Journal article, Peer reviewed
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Date
2022Metadata
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- Department of Biomedicine [710]
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Abstract
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.