Structural Basis for Chaperone-Independent Ubiquitination of Tau Protein by Its E3 Ligase CHIP.
Angew Chem Int Ed Engl
; 61(15): e202112374, 2022 04 04.
Article
em En
| MEDLINE
| ID: mdl-35107860
ABSTRACT
The multi-site ubiquitination of Tau protein found in Alzheimer's disease filaments hints at the failed attempt of neurons to remove early toxic species. The ubiquitin-dependent degradation of Tau is regulated in vivo by the E3 ligase CHIP, a quality controller of the cell proteome dedicated to target misfolded proteins for degradation. In our study, by using site-resolved NMR, biochemical and computational methods, we elucidate the structural determinants underlying the molecular recognition between the ligase and its intrinsically disordered substrate. We reveal a multi-domain dynamic interaction that explains how CHIP can direct ubiquitination of Tau at multiple sites even in the absence of chaperones, including its typical partner Hsp70/Hsc70. Our findings thus provide mechanistic insight into the chaperone-independent engagement of a disordered protein by its E3 ligase.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas tau
/
Ubiquitina-Proteína Ligases
Idioma:
En
Revista:
Angew Chem Int Ed Engl
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Itália