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1.
J Biol Chem ; 290(20): 12487-96, 2015 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-25770209

RESUMEN

The phospho-binding protein 14-3-3ζ acts as a signaling hub controlling a network of interacting partners and oncogenic pathways. We show here that lysines within the 14-3-3ζ binding pocket and protein-protein interface can be modified by acetylation. The positive charge on two of these lysines, Lys(49) and Lys(120), is critical for coordinating 14-3-3ζ-phosphoprotein interactions. Through screening, we identified HDAC6 as the Lys(49)/Lys(120) deacetylase. Inhibition of HDAC6 blocks 14-3-3ζ interactions with two well described interacting partners, Bad and AS160, which triggers their dephosphorylation at Ser(112) and Thr(642), respectively. Expression of an acetylation-refractory K49R/K120R mutant of 14-3-3ζ rescues both the HDAC6 inhibitor-induced loss of interaction and Ser(112)/Thr(642) phosphorylation. Furthermore, expression of the K49R/K120R mutant of 14-3-3ζ inhibits the cytotoxicity of HDAC6 inhibition. These data demonstrate a novel role for HDAC6 in controlling 14-3-3ζ binding activity.


Asunto(s)
Proteínas 14-3-3/metabolismo , Histona Desacetilasas/metabolismo , Proteínas 14-3-3/genética , Acetilación , Sustitución de Aminoácidos , Sitios de Unión , Supervivencia Celular/genética , Proteínas Activadoras de GTPasa/genética , Proteínas Activadoras de GTPasa/metabolismo , Células HEK293 , Histona Desacetilasa 6 , Histona Desacetilasas/genética , Humanos , Lisina/genética , Lisina/metabolismo , Mutación Missense , Proteína Letal Asociada a bcl/genética , Proteína Letal Asociada a bcl/metabolismo
2.
Mol Cell Biol ; 37(20)2017 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-28739857

RESUMEN

In this study, we employed proteomics to identify mechanisms of posttranslational regulation on cell survival signaling proteins. We focused on Cu-Zn superoxide dismutase (SOD1), which protects cells from oxidative stress. We found that acylation of K122 on SOD1, while not impacting SOD1 catalytic activity, suppressed the ability of SOD1 to inhibit mitochondrial metabolism at respiratory complex I. We found that deacylase depletion increased K122 acylation on SOD1, which blocked the suppression of respiration in a K122-dependent manner. In addition, we found that acyl-mimicking mutations at K122 decreased SOD1 accumulation in mitochondria, initially hinting that SOD1 may inhibit respiration directly within the intermembrane space (IMS). However, surprisingly, we found that forcing the K122 acyl mutants into the mitochondria with an IMS-targeting tag did not recover their ability to suppress respiration. Moreover, we found that suppressing or boosting respiration levels toggled SOD1 in or out of the mitochondria, respectively. These findings place SOD1-mediated inhibition of respiration upstream of its mitochondrial localization. Lastly, deletion-rescue experiments show that a respiration-defective mutant of SOD1 is also impaired in its ability to rescue cells from toxicity caused by SOD1 deletion. Together, these data suggest a previously unknown interplay between SOD1 acylation, metabolic regulation, and SOD1-mediated cell survival.


Asunto(s)
Acilación/fisiología , Mitocondrias/metabolismo , Membranas Mitocondriales/metabolismo , Mutación/genética , Superóxido Dismutasa-1/metabolismo , Superóxido Dismutasa/metabolismo , Acilación/genética , Esclerosis Amiotrófica Lateral/genética , Animales , Humanos , Ratones , Mitocondrias/genética , Estrés Oxidativo/fisiología , Superóxido Dismutasa/genética , Superóxido Dismutasa-1/química , Superóxido Dismutasa-1/genética
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