Proc Natl Acad Sci U S A. 2010 Jul 20;107(29):12860-5


F. Javier Pérez-Victoria(1)*, Guillermo Abascal-Palacios(2)*, Igor Tascón(2), Andrey Kajava(3), Javier G. Magadán(1), Erik P. Pioro(4), Juan S. Bonifacino(1), Aitor Hierro(2) *Equal contribution. (1) Cell Biology and Metabolism Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA (2)Structural Biology Unit, CIC bioGUNE, Bizkaia Technology Park, 48160 Derio, Spain. (3)Centre de Recherches de Biochimie Macromoléculaire, CNRS, University of Montpellier, 34293 Montpellier, France. (4)Neuromuscular Center, Neurological Institute, Cleveland Clinic, Cleveland, OH 44195, USA


El complejo GARP está involucrado en el amarre y fusión de vesículas provenientes de endosomas a la red trans-Golgi. La mutación L967Q en la proteína Vps54, uno de los componentes de GARP, es responsable de la degeneración motoneuronal en el modelo de ratón wobbler. Nuestros resultados muestran la estructura cristalográfica del fragmento C-terminal de Vps54 donde la leucina-967 establece interacciones críticas para el mantenimiento de la estabilidad y plegamiento. La mutación no impide la integración de Vps54 en el complejo GARP, sin embargo su vida media se ve drásticamente reducida in vivo. Concluimos que el fenotipo wobbler es causado por la desestabilización de la proteína Vps54 dando lugar a niveles reducidos no solo de esta proteína sino también del complejo GARP.


Imagen artículo Septiembre

El transporte de biomoléculas (proteínas, lípidos y otras macromoléculas) entre los diferentes compartimentos celulares esta mediado mayoritariamente por vesículas. La formación de vesículas en los orgánulos de origen es regulada por una compleja maquinaria de proteínas que forman el "coat", mientras que la fusión con el orgánulo de destino es mediada por la interacción entre SNAREs de la vesícula y de la membrana diana. Otros componentes como GTPasas junto con sus efectores, los factores de amarre, también cooperan con los SNAREs en este proceso. De hecho, la primera interacción física entre la vesícula de transporte y la membrana diana es establecida por los factores de amarre. Como consecuencia, la especificidad en el transporte vesicular está determinada por la combinación de SNAREs, GTPasas, y factores de amarre. El laboratorio de Aitor Hierro en la Unidad de Biología Estructural del CIC-bioGUNE trabaja en determinar mecanísticamente la especificidad de este proceso y su regulación. Para el análisis de los complejos proteicos que actúan en el proceso se utiliza como herramienta principal la cristalografía de rayos-x en combinación con técnicas bioquímicas, biofísicas y de biología celular.

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