期刊
FASEB JOURNAL
卷 34, 期 5, 页码 7192-7207出版社
WILEY
DOI: 10.1096/fj.202000110R
关键词
ganglioside-induced differentiation-associated protein 1; mitochondria; oxidative stress; structural biology; X-ray crystallography
资金
- NIH HHS [S10 OD021540] Funding Source: Medline
- NINDS NIH HHS [R21 NS094860] Funding Source: Medline
- HHS | NIH | NIH Office of the Director (OD) [1S10OD021540] Funding Source: Medline
- HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS) [NS094860] Funding Source: Medline
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 alpha-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.
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