Bienvenidos a CienciaPR, una red de recursos para todos los interesados en las ciencias y en Puerto Rico.
I graduated from Colegio San Ignacio de Loyola (1983); attended Syracuse University for a Bachelors degree in Biochemistry (1987); went on to do a biochemistry PhD thesis at the University of California, Berkeley with Randy Schekman (1993); then spent a few years at Rockefeller University in NYC as a cell biology postdoctoral fellow in Günter Blobel's Lab (1997), then spent eight years as an Assistant Professor at Stanford University (2005), and recently moved to the University of California, Santa Cruz where I am currently an Associate Professor. We apply techniques in biochemistry, cell biology, genetics, proteomics, biophysics, structural biology computational biology and evolution to address the structure and function of a macromolecular machine in cells termed the nuclear pore complex, which controls all nucleo-cytoplasmic transport and communication in eukaryotic cells. Aunque me desarollé como científico y me he pasado la vida científica fuera de Puerto Rico, siempre me quedé con la ansiedad de vivir en la Isla y ser científico allí, junto a mi familia. Pues lo unico trágico de mi profesión ha sido tener que ejercitarla en la ausencia de mi gente, y sin contribuír grándemente a la educación de estudiantes puertoriqueños. Hoy por hoy, para remediar esa situación y para contribuír algo al desarollo de científicos puertoriqueños, yo ofrezco oportunidades de trabajo de verano para estudiantes talentosos que quieran trabajar en mi laboratorio durante dos meses. De esa forma, traigo un poquito de Puerto Rico a mi ambiente local, y ayudo al crecimiento de un boricua científico. Además, estoy dispuesto a aconsejar a cualquier cientifico puertoriquño, ya sea jóven de bachillerato, o de doctorado, o de postdoctorado, especialmente si quieren desarrollar una carrera académica profesional.
Structure and Function of the Nuclear Pore Complex
The nuclear pore complex (NPC) is a supramolecular protein structure in the nuclear envelope that creates a forty-nanometer channel connecting the cytoplasm and nucleoplasm of eukaryotic cells. Its main function is to regulate the vital flow of proteins and RNA between these two major compartments. Small metabolites diffuse freely across the NPC, but the flow of most proteins and RNA is selective and requires specific transit signals. The signals are recognized by mobile receptors termed karyopherins (also called importins, exportins and transportins), which interact with proteins of the NPC (nucleoporins; Nups) to shuttle cargo across the NPC. The process requires thermal energy to operate the NPC machinery, and chemical energy to impart directionality to the transport process via the Ran GTPase.
Research in my lab focuses on two fundamental aspects of nucleocytoplasmic transport:
I. The mechanics of karyopherin movement across the NPC
II. The structure of the NPC transport conduit
We are addressing these topics using a combination of cell biological, biochemical, biophysical, structural, genetic, and molecular modeling techniques in the model eukaryote S. cerevisiae.
I. Mechanics of karyopherin transport across the nuclear pore complex
Many karyopherins and their cargo have been identified but a mechanistic description of how they are mobilized within the NPC is lacking. Each NPC contains more than 200 potential docking sites for karyopherins (provided by nucleoporins that contain FG repeats), so movement of karyopherin-cargo complexes across the NPC is envisioned to be a stochastic process that operates via repeated association-dissociation reactions of karyopherins with FG nucleoporins. Currently, we are charting the path of transport used by karyopherins within the NPC through the identification of nucleoporins that physically contact them in situ within the NPC transport conduit. We are also addressing the kinetics of karyopherin transport across the NPC by characterizing the dynamics of association and dissociation between karyopherins, cargos and nucleoporins, and by identifying factors (KaRFs) that function to accelerate the dissociation rate of the most stable, long-lived intermediate complexes in the transport processes.
Architecture of the NPC transport conduit
Although the mechanics of karyopherin-mediated transport across the NPC are still poorly understood, it is clear that interactions between karyopherins and FG Nups are central to the translocation process. Thus, knowledge of the structural characteristics of FG nucleoporins may explain how karyopherin-cargo complexes of different shapes and sizes can translocate across the NPC while its permeability barrier remains intact. We are characterizing the structure of individual FG nucleoporins using biophysical, structural and molecular modeling techniques. We find that FG repeat regions of Nups are largely devoid of secondary structure and are mostly random coils 200-700 amino acids in length. Thus, the ~200 FG Nups present in each NPC likely form a flexible and highly amorphous meshwork of filaments at its center, which captures and engulfs karyopherin-cargo complexes of different shapes and sizes as they move across the NPC. We are currently testing the notion that FG Nups self-assemble into a meshwork of filaments held together by weak hydrophobic interactions between FG repeats.
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