Premium
Structural and functional divergence of GDAP1 from the glutathione S‐transferase superfamily
Author(s) -
Googins Matthew R.,
WoghirenAfegbua Aigbirhemwen O.,
Calderon Michael,
St. Croix Claudette M.,
Kiselyov Kirill I.,
VanDemark Andrew P.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.202000110r
Subject(s) - glutathione , biochemistry , biology , transmembrane domain , phenotype , chemistry , microbiology and biotechnology , enzyme , receptor , gene
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.