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1.
J Cell Biol ; 179(1): 151-64, 2007 Oct 08.
Artículo en Inglés | MEDLINE | ID: mdl-17923534

RESUMEN

Kidney development and physiology require polarization of epithelia that line renal tubules. Genetic studies show that polarization of invertebrate epithelia requires the crumbs, partition-defective-3, and discs large complexes. These evolutionarily conserved protein complexes occur in mammalian kidney; however, their role in renal development remains poorly defined. Here, we find that mice lacking the small PDZ protein mammalian LIN-7c (MALS-3) have hypomorphic, cystic, and fibrotic kidneys. Proteomic analysis defines MALS-3 as the only known core component of both the crumbs and discs large cell polarity complexes. MALS-3 mediates stable assembly of the crumbs tight junction complex and the discs large basolateral complex, and these complexes are disrupted in renal epithelia from MALS-3 knockout mice. Interestingly, MALS-3 controls apico-basal polarity preferentially in epithelia derived from metanephric mesenchyme, and defects in kidney architecture owe solely to MALS expression in these epithelia. These studies demonstrate that defects in epithelial cell polarization can cause cystic and fibrotic renal disease.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Riñón/patología , Complejos Multiproteicos/fisiología , Proteínas Adaptadoras Transductoras de Señales/fisiología , Secuencia de Aminoácidos , Animales , Moléculas de Adhesión Celular/metabolismo , Moléculas de Adhesión Celular/fisiología , Proteínas de Ciclo Celular , Células Epiteliales/metabolismo , Riñón/embriología , Riñón/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/fisiología , Ratones , Ratones Noqueados , Datos de Secuencia Molecular , Complejos Multiproteicos/genética , Complejos Multiproteicos/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Proteínas del Tejido Nervioso/fisiología , Organogénesis/genética , Subunidades de Proteína/genética , Subunidades de Proteína/metabolismo , Alineación de Secuencia , Uniones Estrechas/metabolismo , Uniones Estrechas/patología
2.
Sci Rep ; 12(1): 17809, 2022 Oct 24.
Artículo en Inglés | MEDLINE | ID: mdl-36280680

RESUMEN

X-ray free-electron lasers (XFELs) as the world's brightest light sources provide ultrashort X-ray pulses with a duration typically in the order of femtoseconds. Recently, they have approached and entered the attosecond regime, which holds new promises for single-molecule imaging and studying nonlinear and ultrafast phenomena such as localized electron dynamics. The technological evolution of XFELs toward well-controllable light sources for precise metrology of ultrafast processes has been, however, hampered by the diagnostic capabilities for characterizing X-ray pulses at the attosecond frontier. In this regard, the spectroscopic technique of photoelectron angular streaking has successfully proven how to non-destructively retrieve the exact time-energy structure of XFEL pulses on a single-shot basis. By using artificial intelligence techniques, in particular convolutional neural networks, we here show how this technique can be leveraged from its proof-of-principle stage toward routine diagnostics even at high-repetition-rate XFELs, thus enhancing and refining their scientific accessibility in all related disciplines.

3.
Neuron ; 52(2): 307-20, 2006 Oct 19.
Artículo en Inglés | MEDLINE | ID: mdl-17046693

RESUMEN

Trafficking of AMPA receptors (AMPA-Rs) to and from synapses controls the strength of excitatory synaptic transmission. However, proteins that cluster AMPA-Rs at synapses remain poorly understood. Here we show that PSD-95-like membrane-associated guanylate kinases (PSD-MAGUKs) mediate this synaptic targeting, and we uncover a remarkable functional redundancy within this protein family. By manipulating endogenous neuronal PSD-MAGUK levels, we find that both PSD-95 and PSD-93 independently mediate AMPA-R targeting at mature synapses. We also reveal unanticipated synapse heterogeneity as loss of either PSD-95 or PSD-93 silences largely nonoverlapping populations of excitatory synapses. In adult PSD-95 and PSD-93 double knockout animals, SAP-102 is upregulated and compensates for the loss of synaptic AMPA-Rs. At immature synapses, PSD-95 and PSD-93 play little role in synaptic AMPA-R clustering; instead, SAP-102 dominates. These studies establish a PSD-MAGUK-specific regulation of AMPA-R synaptic expression that establishes and maintains glutamatergic synaptic transmission in the mammalian central nervous system.


Asunto(s)
Diferenciación Celular/fisiología , Espinas Dendríticas/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas de la Membrana/metabolismo , Receptores AMPA/metabolismo , Sinapsis/metabolismo , Transmisión Sináptica/fisiología , Animales , Células COS , Células Cultivadas , Chlorocebus aethiops , Espinas Dendríticas/ultraestructura , Homólogo 4 de la Proteína Discs Large , Regulación hacia Abajo/fisiología , Ácido Glutámico/metabolismo , Guanilato-Quinasas , Hipocampo/embriología , Hipocampo/metabolismo , Hipocampo/ultraestructura , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas de la Membrana/genética , Ratones , Ratones Noqueados , Neuropéptidos/genética , Neuropéptidos/metabolismo , Técnicas de Cultivo de Órganos , Transporte de Proteínas/fisiología , Ratas , Agregación de Receptores/fisiología , Sinapsis/ultraestructura , Membranas Sinápticas/metabolismo , Membranas Sinápticas/ultraestructura
4.
Nucleic Acids Res ; 33(16): 5362-70, 2005.
Artículo en Inglés | MEDLINE | ID: mdl-16177183

RESUMEN

RNA editing by A-to-I modification has been recognized as an important molecular mechanism for generating RNA and protein diversity. In mammals, it is mediated by a family of adenosine deaminases that act on RNAs (ADARs). The large version of the editing enzyme ADAR1 (ADAR1-L), expressed from an interferon-responsible promoter, has a Z-DNA/Z-RNA binding domain at its N-terminus. We have tested the in vitro ability of the enzyme to act on a 50 bp segment of dsRNA with or without a Z-RNA forming nucleotide sequence. A-to-I editing efficiency is markedly enhanced in presence of the sequence favoring Z-RNA. In addition, an alteration in the pattern of modification along the RNA duplex becomes evident as reaction times decrease. These results suggest that the local conformation of dsRNA molecules might be an important feature for target selectivity by ADAR1 and other proteins with Z-RNA binding domains.


Asunto(s)
Adenosina Desaminasa/metabolismo , Edición de ARN , ARN Bicatenario/química , ARN Bicatenario/metabolismo , Línea Celular , Interpretación Estadística de Datos , Humanos , Conformación de Ácido Nucleico , Proteínas de Unión al ARN , Especificidad por Sustrato
5.
Annu Rev Biochem ; 74: 219-45, 2005.
Artículo en Inglés | MEDLINE | ID: mdl-15952887

RESUMEN

Tissue development, differentiation, and physiology require specialized cellular adhesion and signal transduction at sites of cell-cell contact. Scaffolding proteins that tether adhesion molecules, receptors, and intracellular signaling enzymes organize macromolecular protein complexes at cellular junctions to integrate these functions. One family of such scaffolding proteins is the large group of membrane-associated guanylate kinases (MAGUKs). Genetic studies have highlighted critical roles for MAGUK proteins in the development and physiology of numerous tissues from a variety of metazoan organisms. Mutation of Drosophila discs large (dlg) disrupts epithelial septate junctions and causes overgrowth of imaginal discs. Similarly, mutation of lin-2, a related MAGUK in Caenorhabditis elegans, blocks vulval development, and mutation of the postsynaptic density protein PSD-95 impairs synaptic plasticity in mammalian brain. These diverse roles are explained by recent biochemical and structural analyses of MAGUKs, which demonstrate their capacity to assemble well--efined--yet adaptable--protein complexes at cellular junctions.


Asunto(s)
Adhesión Celular/fisiología , Uniones Intercelulares/enzimología , Nucleósido-Fosfato Quinasa/fisiología , Empalme Alternativo , Animales , Polaridad Celular , Guanilato-Quinasas , Modelos Biológicos , Modelos Moleculares , Plasticidad Neuronal , Nucleósido-Fosfato Quinasa/química , Nucleósido-Fosfato Quinasa/genética , Procesamiento Proteico-Postraduccional , Estructura Cuaternaria de Proteína , Estructura Terciaria de Proteína , Transducción de Señal , Sinapsis/enzimología , Uniones Estrechas/enzimología
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