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Summary: The Vale Lab combines cell biological and biophysical approaches to understand the cytoskeleton and more general issues on spatial organization and movement within cells. The lab, which relies heavily on microscopy, studies these questions at different scales and using different techniques. At the smallest scale, we wish to understand the workings of protein machines. A particular focus has been on microtubule-based "motor proteins", 10-50 nm size proteins, that convert energy from ATP hydrolysis into unidirectional motion and force. However, we also are studying the mechanism of other types of proteins, such as microtubule severing proteins, proteins that localize dynamically to growing plus ends of microtubules (+TIPs), and motor regulatory proteins. Our approach towards dissecting how these proteins operate is to reconstitute and study their activities using in vitro assays, and then apply a spectrum of biophysical tools (e.g. single molecule observation, spectroscopy (e.g. FRET) to peer into lives of these small machines. We also rely heavily on detailed structural information to generate models, which we gather from x-ray crystallography or electron microscopy (studies generated by individuals in the lab or through collaborations). In all cases, we feel that it is essential to be able to produce recombinant proteins for structure-function studies. Then, we can generate hypotheses of how these proteins work (often based upon their structures), design new proteins with predicted new capabilities, and then test if these hypotheses are born out by detailed biophysical analyses of these engineered machines. The ability to engineer protein machines is extremely powerful for deciphering their mechanisms and learning more general lessons about protein design which could potentially be applies to protein therapeutics in vitro.
We wish to understand how collections of these protein machines function together to generate complex behavior in living cells. As examples, we are currently interested in how numerous cytoskeletal and regulatory proteins construct and contribute to the function of the mitotic spindle. We also are interested in cell shape determination (contributing in a modest way to the efforts of the Cell Migration Consortium and The Cell Propulsion Lab at UCSF. Many of these efforts are centered around using large scale (e.g. whole genome RNAi screens) in conjunction with good old fashioned cell biology (step-by-step, intuition-driven investigations of how proteins discovered through screening contribute to cellular function). Many of these efforts involve high throughput imaging, creating data base infrastructure for information storage/retrieval, and MatLab-based analysis of images. We also have become interested in how signaling molecules are organized in the plasma membranes (mainly using T cells, but likely extending to other systems). To assist with all of the above efforts, we use TIRF imaging (including single molecule in living cells), spinning disk confocal, two-photon microscopy, employing short (100 frame/sec) and long (2 day) time scale image acquisition to probe the behavior of cells and subcellular structures.
Recent Vale lab publications
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