RT Journal Article
SR Electronic
T1 Structural insights into Charcot-Marie-Tooth disease-linked mutations in human GDAP1
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.02.18.481076
DO 10.1101/2022.02.18.481076
A1 Aleksi Sutinen
A1 Giang Thi Tuyet Nguyen
A1 Arne Raasakka
A1 Gopinath Muruganandam
A1 Remy Loris
A1 Emil Ylikallio
A1 Henna Tyynismaa
A1 Luca Bartesaghi
A1 Salla Ruskamo
A1 Petri Kursula
YR 2022
UL http://biorxiv.org/content/early/2022/02/18/2022.02.18.481076.abstract
AB 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 as well as CMT2K-linked R120W, both of which are autosomal dominant mutations. The disease variant proteins retain close to normal structure and solution behaviour, but both present a large decrease in thermal stability. Using GDAP1 variant crystal structures, we identify a side chain interaction network between helices α3, α6, and α7, which is affected by CMT mutations, as well as a hinge in the long helix α6, 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.Competing Interest StatementThe authors have declared no competing interest.