We work at the interface of structural biology, cell biology, and protein engineering to understand molecular mechanisms of signal transduction within the human immune system, with the long-term goal of enabling new therapeutic approaches to modulate immune cell function.
Receptors on B cells
The B cell receptor (BCR) signaling pathway is responsible for the production of antibodies and is frequently dysregulated in B cell cancers and autoimmune diseases. We are interested in understanding how receptors on B cells signal to regulate activation of the BCR signaling pathway. We are using structural biology techniques including cryo-electron microscopy and x-ray crystallography, along with cell-based assays and protein engineering to develop new tools to interrogate receptor function and therapeutic potential.
Tetraspanins are a large, highly conserved family of four pass transmembrane proteins that modulate essential signal transduction pathways within the immune system, regulating functions such as pathogen uptake, proliferation, and immunological synapse formation. Whereas many transmembrane proteins bind small molecule or protein ligands to execute their function, tetraspanins do not have an obvious receptor function. Instead, tetraspanins bind a specific partner protein to facilitate its localization in the membrane and association with signaling effectors. Our recent work has shown that tetraspanins are a conformationally regulated family of membrane proteins (Susa et al., 2021). To understand this plasticity at the molecular level, we are using structural biology techniques including cryo-electron microscopy to characterize other tetraspanin-partner complexes and explain how tetraspanins bind to a wide variety of remarkably different protein families.
Dynamics of receptor signaling
We are interested in mapping temporal sequences of protein interactions that drive immune cell signaling pathways. We have taken advantage of recent developments in proximity labeling technology and multiplexed mass spectrometry to engineer a system that allows parallel quantification of B cell co-receptor interactions at distinct time points after B cell activation within a native cellular environment and at native expression levels. This approach has allowed us to identify potential novel mediators of BCR signaling involved in rapid metabolic reprogramming and cytoskeletal regulation upon B cell activation, and our future work will focus on the validation and functional characterization of these candidate proteins.