Structural insights into Charcot–Marie–Tooth disease‐linked mutations in human GDAP1
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 CMT...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-07-01
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| Series: | FEBS Open Bio |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/2211-5463.13422 |
| _version_ | 1811317878235856896 |
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| author | Aleksi Sutinen Giang Thi Tuyet Nguyen Arne Raasakka Gopinath Muruganandam Remy Loris Emil Ylikallio Henna Tyynismaa Luca Bartesaghi Salla Ruskamo Petri Kursula |
| author_facet | Aleksi Sutinen Giang Thi Tuyet Nguyen Arne Raasakka Gopinath Muruganandam Remy Loris Emil Ylikallio Henna Tyynismaa Luca Bartesaghi Salla Ruskamo Petri Kursula |
| author_sort | Aleksi Sutinen |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T12:16:01Z |
| format | Article |
| id | doaj.art-4e1bc0752cf64ca19c72433a691f3831 |
| institution | Directory Open Access Journal |
| issn | 2211-5463 |
| language | English |
| last_indexed | 2024-04-13T12:16:01Z |
| publishDate | 2022-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | FEBS Open Bio |
| spelling | doaj.art-4e1bc0752cf64ca19c72433a691f38312022-12-22T02:47:22ZengWileyFEBS Open Bio2211-54632022-07-011271306132410.1002/2211-5463.13422Structural insights into Charcot–Marie–Tooth disease‐linked mutations in human GDAP1Aleksi Sutinen0Giang Thi Tuyet Nguyen1Arne Raasakka2Gopinath Muruganandam3Remy Loris4Emil Ylikallio5Henna Tyynismaa6Luca Bartesaghi7Salla Ruskamo8Petri Kursula9Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu University of Oulu FinlandFaculty of Biochemistry and Molecular Medicine & Biocenter Oulu University of Oulu FinlandDepartment of Biomedicine University of Bergen NorwayVIB‐VUB Center for Structural Biology Vlaams Instituut voor Biotechnologie Brussels BelgiumVIB‐VUB Center for Structural Biology Vlaams Instituut voor Biotechnologie Brussels BelgiumStem Cells and Metabolism Research Program Faculty of Medicine University of Helsinki FinlandStem Cells and Metabolism Research Program Faculty of Medicine University of Helsinki FinlandDepartment of Neuroscience Karolinska Institutet SwedenFaculty of Biochemistry and Molecular Medicine & Biocenter Oulu University of Oulu FinlandFaculty of Biochemistry and Molecular Medicine & Biocenter Oulu University of Oulu FinlandCharcot–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.https://doi.org/10.1002/2211-5463.13422Charcot–Marie–Tooth diseaseGDAP1GST superfamilyprotein structureneuropathystability |
| spellingShingle | Aleksi Sutinen Giang Thi Tuyet Nguyen Arne Raasakka Gopinath Muruganandam Remy Loris Emil Ylikallio Henna Tyynismaa Luca Bartesaghi Salla Ruskamo Petri Kursula Structural insights into Charcot–Marie–Tooth disease‐linked mutations in human GDAP1 FEBS Open Bio Charcot–Marie–Tooth disease GDAP1 GST superfamily protein structure neuropathy stability |
| title | Structural insights into Charcot–Marie–Tooth disease‐linked mutations in human GDAP1 |
| title_full | Structural insights into Charcot–Marie–Tooth disease‐linked mutations in human GDAP1 |
| title_fullStr | Structural insights into Charcot–Marie–Tooth disease‐linked mutations in human GDAP1 |
| title_full_unstemmed | Structural insights into Charcot–Marie–Tooth disease‐linked mutations in human GDAP1 |
| title_short | Structural insights into Charcot–Marie–Tooth disease‐linked mutations in human GDAP1 |
| title_sort | structural insights into charcot marie tooth disease linked mutations in human gdap1 |
| topic | Charcot–Marie–Tooth disease GDAP1 GST superfamily protein structure neuropathy stability |
| url | https://doi.org/10.1002/2211-5463.13422 |
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