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We Study How Macromolecular and Supramolecular Protein Complexes Regulate Cell Functions by Integrating and
Transducing Signals

All cells must integrate and transduce multiple extracellular signals to achieve an appropriate functional response and phenotype. To perform these complex functions, cells form multiprotein complexes at the right time and with the correct spatial localization. These macromolecular structures integrate and transduce signals via modifications in their composition, by orchestrating subtle changes in the relationships between member proteins, and by being organized into larger supramolecular structures. We are interested in how multiprotein complexes, particularly those formed by transient, low affinity interactions, regulate critical cellular processes in inflammation and leukocyte differentiation. We study how macromolecular organization, distinct from functions of individual proteins, controls biological and biochemical functions. We combine molecular imaging approaches with biochemical and cell biology approaches. These include Fluorescence Lifetime Imaging Microscopy (FLIM), Stochastic Optical Reconstruction Microscopy (N-STORM), SILAC labeling, crosslinking, affinity chromatography and mass spectrometry. A goal of our work is to develop approaches to understanding macromolecular organization in cell biological systems and in vivo models. Disordered protein interactions, either structural or temporal, that lead to “disorganization” of multiprotein complexes may be the basis of many human diseases ranging from the initiation of inflammation in autoimmune disorders, to chronic neurodegenerative, cystic fibrosis, and kidney diseases. Ultimately, understanding the functions of these complexes will be key to understanding the interface between genomics and biochemical mechanisms of disease.

N-STORM superresolution microscopic analysis of the clustering of FcεR1 on the surface of RBL-2H3 cells after stimulation with IgE and antigen.Assembly of the leukotriene synthetic complex on the nuclear membrane


The multiprotein leukotriene (LT) synthetic complex integrates and transduces extracellular signals on the nuclear membrane of myeloid cells to generate the chemotactic lipid LTB₄ and the parent cysteinyl leukotriene LTC₄ from arachidonic acid (AA). As is now recognized for many signaling complexes, the transient assembly of the LT synthetic complex is governed by weak interactions between its members. We study the composition and assembly of this complex, and its further organization into supramolecular nanoclusters.
We have found an unanticipated requirement for the myeloid cell inhibitory receptor CD200R1 in the replication of Herpes Simplex Virus-1 (HSV-1), both in a mouse model of encephalitis and in CD200R1 KO cells. CD200R1 selectively “licensed” pro-inflammatory signaling by TLR2, a known receptor for HSV-1. We study the molecular mechanisms by which CD200R1 controls HSV-1 replication and licenses TLR2 signaling in vivo and in cells; we are developing therapeutic approaches for diseases caused by HSV-1 and related viruses.