7q6k
From Proteopedia
Crystal structure of the human GDAP1 CMT2 mutant-R120W
Structural highlights
DiseaseGDAP1_HUMAN Autosomal recessive Charcot-Marie-Tooth disease with hoarseness;Autosomal recessive intermediate Charcot-Marie-Tooth disease type A;Charcot-Marie-Tooth disease type 2H;Autosomal dominant Charcot-Marie-Tooth disease type 2K;Charcot-Marie-Tooth disease type 4A. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. FunctionGDAP1_HUMAN Regulates the mitochondrial network by promoting mitochondrial fission.[1] Publication Abstract from PubMedCharcot-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 âº3, âº6, and âº7, which is affected by CMT mutations, as well as a hinge in the long helix âº6, 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. Structural insights into Charcot-Marie-Tooth disease-linked mutations in human GDAP1.,Sutinen A, Nguyen GTT, Raasakka A, Muruganandam G, Loris R, Ylikallio E, Tyynismaa H, Bartesaghi L, Ruskamo S, Kursula P FEBS Open Bio. 2022 Jul;12(7):1306-1324. doi: 10.1002/2211-5463.13422. Epub 2022 , May 20. PMID:35509130[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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