Cell Signalling & Trafficking Structures

BIOGRAPHY

ACADEMIC POSITION:
• Professor, Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas
• Chair, Molecular Biophysics Graduate Program

EDUCATION:
• 1981 University of Barcelona BS Organic Chemistry
• 1982 University of Barcelona MS Organic Chemistry
• 1988 University of Barcelona PhD Organic Chemistry
• 1988 University of Barcelona BS Theoretical Physics

MEMBERSHIPS:
• American Chemical Association

HONORS AND AWARDS:
• 1998, Established Investigator Award American Heart Association
• 1983, IV Sant Albert Award for Graduate Research School of Chemistry Graduates, Catalan Chemical Association (Spain)
• 1983, Student Award Catalan Society of Physical, Chemical, and Mathematical Sciences (Spain)

RESEARCH INTERESTS:
The ability of neurons to communicate with each other is fundamental for neural function. Information transfer occurs via neurotransmitters that are released from presynaptic terminals by Ca2+-evoked synaptic vesicle exocytosis and act on receptors in postsynaptic membranes. In addition to triggering exocytosis, Ca2+ regulates the efficiency of release in processes of presynaptic plasticity that mediate some forms of information processing in the brain. Our laboratory is interested in elucidating the mechanisms of neurotransmitter release and its regulation through analysis of the three-dimensional structure and interactions of proteins involved in this process. This research is not only relevant to neurotransmission but also to protein sorting and secretion in general, since most types of intracellular membrane traffic share a common membrane fusion machinery.

Our studies use a wide range of biophysical techniques that include multidimensional NMR spectroscopy, X-ray crystallography, cryo-electron microscopy and fluorescence spectroscopy among others. Our philosophy is to use whichever technique is most suitable to address specific, critical questions that arise as we and others keep making progress in shedding light on to the mechanisms of neurotransmitter release and intracellular membrane fusion in general. This work is performed in close collaboration with several laboratories, in particular those of Thomas Sudhof and Christian Rosenmund, where a variety of neurobiological approaches, including mouse genetics and electrophysiology, are being applied to study neurotransmitter release. The combined expertise from our laboratories allows us to study the mechanism of release using a wide range of techniques, in an endeavor where the structural studies are driven by specific biological questions and the results of these studies in turn drive the biology.

The primary targets of our research can be divided in two groups: i) components of the universal membrane fusion machinery such as the Sec1/Munc18 (SM) homologue munc18-1, the small Rab GTPase Rab3, and the SNARE proteins syntaxin 1, SNAP-25 and synaptobrevin; and ii) proteins with specialized roles in release such as synaptotagmin 1, complexin, munc13 and RIM. Our research has provided key insights into the structures, interactions and functions of these proteins, but we are still far from understanding the mechanisms underlying the different steps that lead to neurotransmitter release, i.e. synaptic vesicle docking, priming of the fusion machinery to a release-ready state, and Ca2+-dependent membrane fusion. After having analyzed the structures and interactions of many of these proteins using soluble fragments that lacked transmembrane regions, we are now focusing on the reconstitution into membranes of the macromolecular assemblies that mediate the different steps of release. A key aspect of these current efforts is the development of methodologies to analyze in detail protein-protein interactions on lipid bilayers.