Ukmar-Godec T, Fang P, Ibáñez de Opakua A, Henneberg F, Godec A, Pan K-T, Cima-Omori M-S, Chari A, Mandelkow E, Urlaub H, Zweckstetter M
German Center for Neurodegenerative Diseases (DZNE), Von-Siebold-Str. 3a, 37075 Göttingen, Germany.
Department of Neurology, University Medical Center Göttingen, University of Göttingen, Waldweg 33, 37073 Göttingen, Germany.
Sci Adv. 2020 Jul 22;6(30):eaba3916. doi: 10.1126/sciadv.aba3916. eCollection 2020 Jul.
Intrinsically disordered proteins (IDPs) can be degraded in a ubiquitin-independent process by the 20 proteasome. Decline in 20 activity characterizes neurodegenerative diseases. Here, we examine 20 degradation of IDP tau, a protein that aggregates into insoluble deposits in Alzheimer's disease. We show that cleavage of tau by the 20 proteasome is most efficient within the aggregation-prone repeat region of tau and generates both short, aggregation-deficient peptides and two long fragments containing residues 1 to 251 and 1 to 218. Phosphorylation of tau by the non-proline-directed Ca/calmodulin-dependent protein kinase II inhibits degradation by the 20 proteasome. Phosphorylation of tau by GSK3β, a major proline-directed tau kinase, modulates tau degradation kinetics in a residue-specific manner. The study provides detailed insights into the degradation products of tau generated by the 20 proteasome, the residue specificity of degradation, single-residue degradation kinetics, and their regulation by posttranslational modification.
内在无序蛋白（IDP）可通过20S蛋白酶体在不依赖泛素的过程中被降解。20S活性下降是神经退行性疾病的特征。在此，我们研究IDP tau的20S降解情况，tau蛋白在阿尔茨海默病中会聚集形成不溶性沉积物。我们发现，20S蛋白酶体对tau的切割在tau易于聚集的重复区域内最为有效，并产生短的、缺乏聚集能力的肽段以及两个包含1至251位残基和1至218位残基的长片段。非脯氨酸定向的钙/钙调蛋白依赖性蛋白激酶II对tau的磷酸化会抑制20S蛋白酶体的降解作用。糖原合成酶激酶3β（一种主要的脯氨酸定向tau激酶）对tau的磷酸化以残基特异性方式调节tau的降解动力学。该研究详细深入地探讨了20S蛋白酶体产生的tau降解产物、降解的残基特异性、单残基降解动力学以及它们通过翻译后修饰的调控情况。
