Assessing the Biochemical Activity of proteins Ganglioside Induced Associated Protein 1 (GDAP1) and its paralog protein GDAP1L1Deng, Andrew L (2024) Assessing the Biochemical Activity of proteins Ganglioside Induced Associated Protein 1 (GDAP1) and its paralog protein GDAP1L1. Master's Thesis, University of Pittsburgh. (Unpublished)
AbstractThe Ganglioside Induced Differentiation Associated Protein (GDAP) family was discovered over two decades ago. Since then, hGDAP1 has been extensively studied as it shares sequence and structural similarities with the Glutathione S-Transferase (GST) superfamily and specific hGDAP1 mutations directly cause Charcot-Marie-Tooth (CMT) disease, a commonly inherited peripheral neuropathy. Despite extensive study, the exact biochemical functions of hGDAP1 remain unclear. Though it resembles a GST, hGDAP1 could not catalyze GST-like thioltransferase activity. In parallel, it was discovered that GDAP1 is associated with other biological processes that are key to cellular homeostasis. However, the biochemical basis behind these activities remains unclear. The discovery of a hGDAP1 paralog, hGDAP1-like protein 1 (GDAP1L1), further complicates the understanding of hGDAP1’s biochemical activity. Though both proteins share several functional similarities, the molecular origins behind hGDAP1L1 activity are also unclear. To assess the biochemical activities of both proteins, Evolutionary and sequence analyses of GDAP1 and GDAP1L1 indicate that both share similarities to Zeta, Theta, Pi, and Omega GSTs, as well as the GST-resembling Chloride Intracellular Channel (CLIC) proteins. Subsequent structural comparisons further revealed that despite their lack of GST-like activity, hGDAP1 and hGDAP1L1 both feature multiple G and H-site residues that may allow them to bind glutathione (GSH) and GSH conjugate molecules, as well as other substrates within their G-sites. Further structural analyses of hGDAP1 and hGDAP1L1 proteins have identified multiple structural features that may be crucial to their biochemical functions. Lastly, structural predictions of hGDAP1 and hGDAP1L1 higher-order assemblies suggest, for the first time, that these proteins may form supramolecular transporter complexes anchored to the mitochondrial outer membrane (OMM). These findings enhance the understanding of GDAP1 and GDAP1L1's structural and functional features and suggest novel mechanisms by which these proteins promote cellular homeostasis. Share
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