6UIH

Crystal structure of the core domain from the GST-like protein GDAP1

Summary for 6UIH

• Entry DOI: 10.2210/pdb6uih/pdb
• Descriptor: Ganglioside-induced differentiation-associated protein 1 (1 entity in total)
• Functional Keywords: thioredoxin, gst-like, gdap1, mitochondrial morphology, signaling protein
• Biological source: Mus musculus (Mouse); More
• Total number of polymer chains: 1
• Total formula weight: 26831.73

Authors

Googins, M.R.,VanDemark, A.P. (deposition date: 2019-09-30, release date: 2020-04-29, Last modification date: 2024-10-16)

Primary citation

Googins, M.R.,Woghiren-Afegbua, A.O.,Calderon, M.,St Croix, C.M.,Kiselyov, K.I.,VanDemark, A.P.
Structural and functional divergence of GDAP1 from the glutathione S-transferase superfamily.
Faseb J., 34:7192-7207, 2020

PubMed Abstract: 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.

PubMed: 32274853
DOI: 10.1096/fj.202000110R

Experimental method

X-RAY DIFFRACTION (2.826 Å)