Small ubiquitin-like modifier (SUMO) modification of natively unfolded proteins tau and alpha-synuclein.
Sumoylation is an important post-translational modification that provides a rapid and reversible means for controlling the activity, subcellular localization, and stability of target proteins. We have examined the covalent attachment of the small ubiquitin-like modifier (SUMO) proteins to tau and alpha-synuclein, two natively unfolded proteins that define several neurodegenerative diseases. Both brain proteins were preferentially modified by SUMO1, as compared with SUMO2 or SUMO3. Tau contains two SUMO consensus sequences, and mutational analyses identified Lys(340) as the major sumoylation site. Although both tau and alpha-synuclein are targets for proteasomal degradation, only tau sumoylation was affected by inhibitors of the proteasome pathway. Tau is a microtubule-associated protein, whose ability to bind and stabilize microtubules is negatively regulated by phosphorylation. Treatment with the phosphatase inhibitor, okadaic acid, or the microtubule depolymerizing drug, colchicine, up-regulated tau sumoylation. This suggests that SUMO modification may preferentially target a free soluble pool of the substrate. These findings revealed a new, possibly regulatory, modification of tau and alpha-synuclein that may also have implications for their pathogenic roles in neurodegenerative diseases.
Dorval
Véronique
V
Department of Medical Biophysics and Centre for Research in Neurodegenerative Diseases, University of Toronto, 6 Queen's Park Crescent West, Toronto, Ontario M5S 3H2, Canada.
Fraser
Paul E
PE
D015153:Blotting, Western; D002460:Cell Line; D000939:Epitopes / Q000737:chemistry; D006801:Humans; D008239:Lysine / Q000737:chemistry; D008870:Microtubules / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000378:metabolism; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D011489:Protein Denaturation; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D025842:SUMO-1 Protein; D025841:Small Ubiquitin-Related Modifier Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D014162:Transfection; D025801:Ubiquitin / Q000737:chemistry; D014452:Ubiquitins / Q000737:chemistry; D051844:alpha-Synuclein / Q000737:chemistry* / Q000378:metabolism; D016875:tau Proteins / Q000737:chemistry* / Q000378:metabolism
D000939:Epitopes; D025842:SUMO-1 Protein; C495501:SUMO1 protein, human; C117909:SUMO2 protein, human; C492189:SUMO3 protein, human; D025841:Small Ubiquitin-Related Modifier Proteins; D025801:Ubiquitin; D014452:Ubiquitins; D051844:alpha-Synuclein; D016875:tau Proteins; D046988:Proteasome Endopeptidase Complex; D008239:Lysine