Structure of the Complete Dimeric Human GDAP1 Core Domain Provides Insights into Ligand Binding and Clustering of Disease Mutations

Nguyen, Giang Thi Tuyet; Sutinen, Aleksi; Raasakka, Arne; Muruganandam, Gopinath; Loris, Remy; Kursula, Petri

doi:10.3389/fmolb.2020.631232

Cited by 11 publications

(89 citation statements)

References 83 publications

(114 reference statements)

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“…Hence, at the resolution of a SAXS experiment, neither mutation caused large-scale conformational changes. The dimer-monomer equilibrium in GDAP1 is dynamic, and the dimeric form is favoured at high concentrations [18]. At the concentrations and conditions used here, GDAP1 exists as a dimer, as indicated by the SAXS data.…”

Section: The Mutant Proteins Show Unaltered Conformation But Lowered ...mentioning

confidence: 70%

“…with one short and one long α6 helix [18]. These observations suggest that the GDAP1-specific insertion is flexible also in solution.…”

Section: Flexibility Of the α6 Helixmentioning

confidence: 70%

“…The dimer-monomer equilibrium in GDAP1 is dynamic, and the dimeric form is favoured at high concentrations [18]. At the concentrations and conditions used here, GDAP1 exists as a dimer, as indicated by the SAXS data.…”

Section: Resultsmentioning

confidence: 99%

“…1A). We previously determined the crystal structure of wild-type GDAP1∆303-358, which corresponds to the GST-like core domain of GDAP1 in dimeric form, including the GDAP1-specific insertion [18].…”

Section: Structural Effects Of Cmt Mutations H123r and R120w On Gdap1mentioning

confidence: 99%

“…Many other CMT mutations cluster into this area [18], affecting a number of residues in an interaction network (Fig. 1A,C).…”

Section: The Mutant Proteins Show Unaltered Conformation But Lowered ...mentioning

confidence: 99%

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Structural insights into Charcot-Marie-Tooth disease-linked mutations in human GDAP1

Sutinen

Nguyen

Raasakka

et al. 2022

Preprint

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Section: The Mutant Proteins Show Unaltered Conformation But Lowered ...mentioning

confidence: 70%

“…with one short and one long α6 helix [18]. These observations suggest that the GDAP1-specific insertion is flexible also in solution.…”

Section: Flexibility Of the α6 Helixmentioning

confidence: 70%

Section: Resultsmentioning

confidence: 99%

Section: Structural Effects Of Cmt Mutations H123r and R120w On Gdap1mentioning

confidence: 99%

“…Many other CMT mutations cluster into this area [18], affecting a number of residues in an interaction network (Fig. 1A,C).…”

Section: The Mutant Proteins Show Unaltered Conformation But Lowered ...mentioning

confidence: 99%

See 3 more Smart Citations

Structural insights into Charcot-Marie-Tooth disease-linked mutations in human GDAP1

Sutinen

Nguyen

Raasakka

et al. 2022

Preprint

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Structural insights into Charcot–Marie–Tooth disease‐linked mutations in human GDAP1

et al. 2022

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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 gangliosideinduced 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.Inherited polyneuropathies are a genetically and clinically diverse group of neurodegenerative diseases affecting motor and sensory neurons in the peripheral nervous system (PNS) [1,2]. Mutations in dozens of genes expressed in the PNS cause Charcot-Marie-Tooth disease (CMT). Based on clinical findings, CMT can be classified into three forms: demyelinating, axonal, and intermediate [3,4]. The progress of CMT is linked to the hereditary pattern, whereby the autosomal recessive form has an earlier onset and more severe symptoms than the autosomal dominant form [5][6][7]. Understanding the molecular function of the proteins involved in the etiology of neuropathies is vital in efforts toward treatment and diagnosis.

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Conformational analysis of membrane-proximal segments of GDAP1 in a lipidic environment using synchrotron radiation suggests a mode of assembly at the mitochondrial outer membrane

Sutinen,

Jones,

Hoffmann

et al. 2023

Biophysical Chemistry

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Structure of the Complete Dimeric Human GDAP1 Core Domain Provides Insights into Ligand Binding and Clustering of Disease Mutations

Cited by 11 publications

References 83 publications

Structural insights into Charcot-Marie-Tooth disease-linked mutations in human GDAP1

Structural insights into Charcot-Marie-Tooth disease-linked mutations in human GDAP1

Structural insights into Charcot–Marie–Tooth disease‐linked mutations in human GDAP1

Conformational analysis of membrane-proximal segments of GDAP1 in a lipidic environment using synchrotron radiation suggests a mode of assembly at the mitochondrial outer membrane

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