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Research:

One of the great quandaries of our age is that despite all our scientific progress, our attempts to improve human lives often seems high-risk, time-intensive and expensive. The genetic code has been deciphered, thousands of genomes have been sequenced, and most protein folds are now known. However, our understanding of how dynamic organelles and living cells are formed is at its infancy, and more effective drug molecules for addressing the unmet needs of patients are ever-more costly to design and deliver.

To address the gaps, we focus on three areas:

1. Extending from the genetic code to a more complete biological code that includes not nucleic acid and protein information but also membrane codes. We have discovered memteins (membrane protein assemblies), regulatory MET-stops and PIP-stops, and the elusive lipidons that dictate membrane reader functions. We are also determining how proteins recognize lipids and reshape membranes. Progress includes the elucidation of how FYVE and PX domains bind the phosphoinositol 3-phosphate lipids found on endosomes, and how PH domains recognize phosphoinositol 4-phosphate on Golgi membranes. Along the way we co-developed predictive "MODA" software for identifying novel membrane binding surfaces on virtually any protein structure and SMALP system for making native nanodiscs. Ultimately we hope to decipher the entirety of the lipid code whereby proteins recognize complex membrane surfaces, shape dynamic organelle structures and initiate localized signaling.
   
   
2. Disease mechanisms of oncogenic proteins, prions, and systems used by viral and bacterial pathogens with an emphasis on those that occur on membranes, as well as effects of critical mutations and modifications. Our targets include the Fgd5 GTPase, CaMK1D kinase, Shp2 phosphatase, tetraspanins including the CD81 receptor for Hepatitis C virus, and desmosomal proteins that mediate cell adhesion and cytoskeletal attachment. We elucidate the structures, dynamics and interactions of these systems, and identify new sites and ligands that can inform the design of novel therapeutic agents.
   
   
3. To reduce the cost of drug discovery and open up entirely new target areas, we are developing tools for the research community. Libraries of molecules including biological signals and drug fragments have been assembled to identify novel pockets and starting points for efficient lead discovery. Biophysical methods including biolayer interferometry, microscale diffusion, isothermal titration calorimetry and nuclear magnetic resonance spectroscopy are being harnessed to identify ligands and binding modes. Polymers are being used to solubilize and study challenging membrane protein targets with styrene maleic acid lipid particles (SMALPs). These tools are shared open access facilities including Molscreen and NANUC, and through consortia including the SMALP Network.
   
   

   Our lab's ethos is team-based and collaborative, and involves international teams and funding from across the world. We partner with industry to address global challenges including tackling novel targets and cancers lacking effective cures, we work with startups to develop new products, and engage with leaders to inform policy and spur innovation.

 

Selected Publications:

Recognition and Remodeling of endosomal zones by sorting nexins
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