Structural and functional divergence of GDAP1 from the glutathione S-transferase superfamily
| Autor: | Claudette M. St. Croix, Aigbirhemwen O Woghiren-Afegbua, Michael J. Calderon, Matthew R Googins, Kirill Kiselyov, Andrew P. VanDemark |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Models Molecular Nerve Tissue Proteins Mitochondrion Crystallography X-Ray Biochemistry Article Substrate Specificity 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Protein Domains Charcot-Marie-Tooth Disease Catalytic Domain Genetics Humans Receptor Protein Structure Quaternary Molecular Biology Glutathione Transferase biology Chemistry Glutathione Phenotype Cell biology Mitochondria Transmembrane domain Oxidative Stress 030104 developmental biology Glutathione S-transferase Structural biology Mutation biology.protein 030217 neurology & neurosurgery Functional divergence Biotechnology HeLa Cells |
| Zdroj: | FASEB J |
| ISSN: | 1530-6860 |
| Popis: | Mutations in ganglioside-induced differentiation-associated protein 1 (GDAP1) alter mitochondrial morphology and result in several subtypes of the inherited peripheral neuropathy Charcot-Marie-Tooth disease; however, the mechanism by which GDAP1 functions has remained elusive. GDAP1 contains primary sequence homology to the GST superfamily; however, the question of whether GDAP1 is an active GST has not been clearly resolved. Here, we present biochemical evidence, suggesting that GDAP1 has lost the ability to bind glutathione without a loss of substrate binding activity. We have revealed that the α-loop, located within the H-site motif is the primary determinant for substrate binding. Using structural data of GDAP1, we have found that critical residues and configurations in the G-site which canonically interact with glutathione are altered in GDAP1, rendering it incapable of binding glutathione. Last, we have found that the overexpression of GDAP1 in HeLa cells results in a mitochondrial phenotype which is distinct from oxidative stress-induced mitochondrial fragmentation. This phenotype is dependent on the presence of the transmembrane domain, as well as a unique hydrophobic domain that is not found in canonical GSTs. Together, we data point toward a non-enzymatic role for GDAP1, such as a sensor or receptor. |
| Databáze: | OpenAIRE |
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