2020
DOI: 10.1101/2020.09.04.283028
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Evolutionarily conserved chaperone-mediated proteasomal degradation of a disease-linked aspartoacylase variant

Abstract: Canavan disease is a severe progressive neurodegenerative disorder that is characterized by swelling and spongy degeneration of brain white matter. The disease is genetically linked to polymorphisms in the aspartoacylase (ASPA) gene, including the substitution C152W. ASPA C152W is associated with greatly reduced protein levels in cells, yet biophysical experiments suggest a wild-type like thermal stability. Here, we examine the stability and degradation pathway of ASPA C152W. When we expressed ASPA C152W in Sa… Show more

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“…This is reasonable because the destabilizing effect of mutations required for triggering protein degradation is rather low (about 8–12 kJ·mol −1 ), well within the achievable ligand-induced stabilization [ 114 , 115 , 116 , 117 , 118 , 119 ]. In other cases, protein degradation may depend on local destabilization of the protein structure, which initiates degradation, rather than in global destabilization [ 120 , 121 , 122 , 123 ]. Consequently, a disease-associated variant may bind and become globally (i.e.…”
Section: Towards the Discovery Of Pharmacological Chaperones For Gmentioning
confidence: 99%
“…This is reasonable because the destabilizing effect of mutations required for triggering protein degradation is rather low (about 8–12 kJ·mol −1 ), well within the achievable ligand-induced stabilization [ 114 , 115 , 116 , 117 , 118 , 119 ]. In other cases, protein degradation may depend on local destabilization of the protein structure, which initiates degradation, rather than in global destabilization [ 120 , 121 , 122 , 123 ]. Consequently, a disease-associated variant may bind and become globally (i.e.…”
Section: Towards the Discovery Of Pharmacological Chaperones For Gmentioning
confidence: 99%