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1.
J Med Chem ; 62(20): 9008-9025, 2019 10 24.
Artículo en Inglés | MEDLINE | ID: mdl-31550156

RESUMEN

Modifications of histone tails, including lysine/arginine methylation, provide the basis of a "chromatin or histone code". Proteins that contain "reader" domains can bind to these modifications and form specific effector complexes, which ultimately mediate chromatin function. The spindlin1 (SPIN1) protein contains three Tudor methyllysine/arginine reader domains and was identified as a putative oncogene and transcriptional coactivator. Here we report a SPIN1 chemical probe inhibitor with low nanomolar in vitro activity, exquisite selectivity on a panel of methyl reader and writer proteins, and with submicromolar cellular activity. X-ray crystallography showed that this Tudor domain chemical probe simultaneously engages Tudor domains 1 and 2 via a bidentate binding mode. Small molecule inhibition and siRNA knockdown of SPIN1, as well as chemoproteomic studies, identified genes which are transcriptionally regulated by SPIN1 in squamous cell carcinoma and suggest that SPIN1 may have a role in cancer related inflammation and/or cancer metastasis.


Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Cromatina/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Sondas Moleculares/química , Fosfoproteínas/metabolismo , Dominio Tudor , Proteínas de Ciclo Celular/química , Línea Celular Tumoral , Cristalografía por Rayos X , Humanos , Proteínas Asociadas a Microtúbulos/química , Fosfoproteínas/química , Conformación Proteica
2.
Cereb Cortex ; 28(4): 1087-1104, 2018 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-28158493

RESUMEN

Dendritic spines compartmentalize information in the brain, and their morphological characteristics are thought to underly synaptic plasticity. Here we identify copine-6 as a novel modulator of dendritic spine morphology. We found that brain-derived neurotrophic factor (BDNF) - a molecule essential for long-term potentiation of synaptic strength - upregulated and recruited copine-6 to dendritic spines in hippocampal neurons. Overexpression of copine-6 increased mushroom spine number and decreased filopodia number, while copine-6 knockdown had the opposite effect and dramatically increased the number of filopodia, which lacked PSD95. Functionally, manipulation of post-synaptic copine-6 levels affected miniature excitatory post-synaptic current (mEPSC) kinetics and evoked synaptic vesicle recycling in contacting boutons, and post-synaptic knockdown of copine-6 reduced hippocampal LTP and increased LTD. Mechanistically, copine-6 promotes BDNF-TrkB signaling and recycling of activated TrkB receptors back to the plasma membrane surface, and is necessary for BDNF-induced increases in mushroom spines in hippocampal neurons. Thus copine-6 regulates BDNF-dependent changes in dendritic spine morphology to promote synaptic plasticity.


Asunto(s)
Proteínas Portadoras/metabolismo , Espinas Dendríticas/fisiología , Hipocampo/citología , Proteínas del Tejido Nervioso/metabolismo , Neuronas/fisiología , Neuronas/ultraestructura , Vesículas Sinápticas/fisiología , Animales , Factor Neurotrófico Derivado del Encéfalo/farmacología , Proteínas Portadoras/genética , Células Cultivadas , Espinas Dendríticas/ultraestructura , Homólogo 4 de la Proteína Discs Large/metabolismo , Humanos , Ratones , Proteínas Asociadas a Microtúbulos/metabolismo , Proteínas del Tejido Nervioso/genética , Técnicas de Cultivo de Órganos , Ratas , Receptor trkB/genética , Receptor trkB/metabolismo , Sinapsis/efectos de los fármacos , Sinapsis/fisiología , Sinapsis/ultraestructura , Potenciales Sinápticos/efectos de los fármacos , Potenciales Sinápticos/genética , Vesículas Sinápticas/efectos de los fármacos , Sinaptosomas/metabolismo , Sinaptosomas/ultraestructura , Proteína 1 de Transporte Vesicular de Glutamato/metabolismo , Proteínas del Transporte Vesicular de Aminoácidos Inhibidores/metabolismo
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