Myopathy associated BAG3 mutations lead to protein aggregation by stalling Hsp70 networks.
Nat Commun
; 9(1): 5342, 2018 12 17.
Article
en En
| MEDLINE
| ID: mdl-30559338
ABSTRACT
BAG3 is a multi-domain hub that connects two classes of chaperones, small heat shock proteins (sHSPs) via two isoleucine-proline-valine (IPV) motifs and Hsp70 via a BAG domain. Mutations in either the IPV or BAG domain of BAG3 cause a dominant form of myopathy, characterized by protein aggregation in both skeletal and cardiac muscle tissues. Surprisingly, for both disease mutants, impaired chaperone binding is not sufficient to explain disease phenotypes. Recombinant mutants are correctly folded, show unaffected Hsp70 binding but are impaired in stimulating Hsp70-dependent client processing. As a consequence, the mutant BAG3 proteins become the node for a dominant gain of function causing aggregation of itself, Hsp70, Hsp70 clients and tiered interactors within the BAG3 interactome. Importantly, genetic and pharmaceutical interference with Hsp70 binding completely reverses stress-induced protein aggregation for both BAG3 mutations. Thus, the gain of function effects of BAG3 mutants act as Achilles heel of the HSP70 machinery.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Músculo Esquelético
/
Proteínas HSP70 de Choque Térmico
/
Proteínas Adaptadoras Transductoras de Señales
/
Proteínas Reguladoras de la Apoptosis
/
Agregación Patológica de Proteínas
/
Enfermedades Musculares
/
Miocardio
Tipo de estudio:
Risk_factors_studies
Límite:
Humans
Idioma:
En
Revista:
Nat Commun
Asunto de la revista:
BIOLOGIA
/
CIENCIA
Año:
2018
Tipo del documento:
Article
País de afiliación:
Países Bajos