Structural insights into Charcot–Marie–Tooth disease‐linked mutations in human GDAP1. Issue 7 (20th May 2022)

• Record Type: Journal Article
• Authors: Sutinen, Aleksi; Nguyen, Giang Thi Tuyet; Raasakka, Arne; Muruganandam, Gopinath; Loris, Remy; Ylikallio, Emil; Tyynismaa, Henna; Bartesaghi, Luca; Ruskamo, Salla; Kursula, Petri
• Is Part Of: FEBS open bio. Volume 12:Issue 7(2022)
• Page Start: 1306
• Page End: 1324
• Publication Date: 2022-05-20
• Subjects: Charcot–Marie–Tooth disease -- GDAP1 -- GST superfamily -- protein structure -- neuropathy -- stability; Molecular biology -- Periodicals; Cytology -- Periodicals; Life sciences -- Periodicals; Biological Science Disciplines -- Periodicals; Molecular Biology -- Periodicals; Cell Biology -- Periodicals; Cytology; Life sciences; Molecular biology; Periodicals; 572.805
• DOI: 10.1002/2211-5463.13422
• Languages: English
• ISSNs: 2211-5463

Abstract

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. Abstract : Charcot–Marie–Tooth disease (CMT) is a hereditary neuropathy in humans, and GDAP1 is a common target for CMT‐linked mutations. Many of the mutation sites in the 3D structure of GDAP1 cluster into a region of intramolecular interactions. We studied in detail two of these mutations: H123R and R120W. We identify changes in mutant GDAP1 structure and stability.