Axotrophin/MARCH7 acts as an E3 ubiquitin ligase and ubiquitinates tau protein in vitro impairing microtubule binding.
Biochim Biophys Acta
; 1842(9): 1527-38, 2014 Sep.
Article
en En
| MEDLINE
| ID: mdl-24905733
ABSTRACT
Tau is the major microtubule-associated protein in neurons involved in microtubule stabilization in the axonal compartment. Changes in tau gene expression, alternative splicing and posttranslational modification regulate tau function and in tauopathies can result in tau mislocalization and dysfunction, causing tau aggregation and cell death. To uncover proteins involved in the development of tauopathies, a yeast two-hybrid system was used to screen for tau-interacting proteins. We show that axotrophin/MARCH7, a RING-variant domain containing protein with similarity to E3 ubiquitin ligases interacts with tau. We defined the tau binding domain to amino acids 552-682 of axotrophin comprising the RING-variant domain. Co-immunoprecipitation and co-localization confirmed the specificity of the interaction. Intracellular localization of axotrophin is determined by an N-terminal nuclear targeting signal and a C-terminal nuclear export signal. In AD brain nuclear localization is lost and axotrophin is rather associated with neurofibrillary tangles. We find here that tau becomes mono-ubiquitinated by recombinant tau-interacting RING-variant domain, which diminishes its microtubule-binding. In vitro ubiquitination of four-repeat tau results in incorporation of up to four ubiquitin molecules compared to two molecules in three-repeat tau. In summary, we present a novel tau modification occurring preferentially on 4-repeat tau protein which modifies microtubule-binding and may impact on the pathogenesis of tauopathies.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Contexto en salud:
6_ODS3_enfermedades_notrasmisibles
Problema de salud:
6_alzheimer_other_dementias
/
6_mental_health_behavioral_disorders
Asunto principal:
Encéfalo
/
Proteínas tau
/
Ubiquitina
/
Ubiquitina-Proteína Ligasas
/
Enfermedad de Alzheimer
/
Microtúbulos
Tipo de estudio:
Observational_studies
/
Risk_factors_studies
Límite:
Aged
/
Animals
/
Humans
Idioma:
En
Revista:
Biochim Biophys Acta
Año:
2014
Tipo del documento:
Article
País de afiliación:
Alemania