3-O-Sulfation of Heparan Sulfate Enhances Tau Interaction and Cellular Uptake.
Angew Chem Int Ed Engl
; 59(5): 1818-1827, 2020 01 27.
Article
en En
| MEDLINE
| ID: mdl-31692167
ABSTRACT
Prion-like transcellular spreading of tau in Alzheimer's Disease (AD) is mediated by tau binding to cell surface heparan sulfate (HS). However, the structural determinants for tau-HS interaction are not well understood. Microarray and SPR assays of structurally defined HS oligosaccharides show that a rare 3-O-sulfation (3-O-S) of HS significantly enhances tau binding. In Hs3st1-/- (HS 3-O-sulfotransferase-1 knockout) cells, reduced 3-O-S levels of HS diminished both cell surface binding and internalization of tau. In a cell culture, the addition of a 3-O-S HS 12-mer reduced both tau cell surface binding and cellular uptake. NMR titrations mapped 3-O-S binding sites to the microtubule binding repeat 2 (R2) and proline-rich region 2 (PRR2) of tau. Tau is only the seventh protein currently known to recognize HS 3-O-sulfation. Our work demonstrates that this rare 3-O-sulfation enhances tau-HS binding and likely the transcellular spread of tau, providing a novel target for disease-modifying treatment of AD and other tauopathies.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Membrana Celular
/
Proteínas tau
/
Enfermedad de Alzheimer
/
Heparitina Sulfato
Límite:
Humans
Idioma:
En
Revista:
Angew Chem Int Ed Engl
Año:
2020
Tipo del documento:
Article
País de afiliación:
Estados Unidos