Abstract
Mutations in the ganglioside-induced differentiation associated protein 1 (GDAP1) cause severe peripheral motor and sensory neuropathies called Charcot-Marie-Tooth disease. GDAP1 expression induces fission of mitochondria and peroxisomes by a currently elusive mechanism, while disease causing mutations in GDAP1 impede the protein’s role in mitochondrial dynamics. In silico analysis reveals sequence similarities of GDAP1 to glutathione S-transferases (GSTs). However, a proof of GST activity and its possible impact on membrane dynamics are lacking to date. Using recombinant protein, we demonstrate for the first time theta-class-like GST activity for GDAP1, and it’s activity being regulated by the C-terminal hydrophobic domain 1 (HD1) of GDAP1 in an autoinhibitory manner. Moreover, we show that the HD1 amphipathic pattern is required to induce membrane dynamics by GDAP1. As both, fission and GST activities of GDAP1, are critically dependent on HD1, we propose that GDAP1 undergoes a molecular switch, turning from a pro-fission active to an auto-inhibited inactive conformation.
Highlights
State, the cytosolic GDAP1like[1] translocates to mitochondria, integrates into the mitochondrial outer membrane (MOM) and causes mitochondrial fission[17]
While full-length Ganglioside-induced differentiation associated protein 1 (GDAP1) cannot be purified in soluble form from E. coli or insect cell, C-terminal truncated recombinant GDAP1 proteins without the C-terminal transmembrane domain (TMD) are readily expressed and soluble
We found that only GDAP1 lacking both its C-terminal TMD and hydrophobic domain 1 (HD1) has GSH-conjugating activity
Summary
State, the cytosolic GDAP1like[1] translocates to mitochondria, integrates into the MOM and causes mitochondrial fission[17]. This translocation and integration of GDAP1like[1] into the MOM is caused by an increase in the concentration of the oxidized form of glutathione in vitro and in vivo where it is capable of substituting for the loss of GDAP1 in the central nervous system of GDAP1-deficient mice[17]. We propose a model of action with two different, interconvertible conformations of GDAP1: a GST active state with an exposed HD1 mediating mitochondrial and peroxisomal fission, and a GST-inactive state caused by an autoinhibitory binding mode of HD1
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