TY - JOUR T1 - Structural insights into Charcot-Marie-Tooth disease-linked mutations in human GDAP1 JF - bioRxiv DO - 10.1101/2022.02.18.481076 SP - 2022.02.18.481076 AU - Aleksi Sutinen AU - Giang Thi Tuyet Nguyen AU - Arne Raasakka AU - Gopinath Muruganandam AU - Remy Loris AU - Emil Ylikallio AU - Henna Tyynismaa AU - Luca Bartesaghi AU - Salla Ruskamo AU - Petri Kursula Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/02/18/2022.02.18.481076.abstract N2 - 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. ER -