Biological Chemistry and Molecular Pharmacology
Our laboratory studies the structural biology of cell signaling and the actin cytoskeleton. Active areas of investigation include: 1) the structure and regulation of focal adhesion kinase, 2) the molecular mechanisms that drive recruitment and activation of Src-family kinases in T-cell activation, and 3) formin proteins and the mechanisms by which they carry out the regulated assembly of actin structures. Additionally, we are studying other signaling interactions that may be targets for development of anti-cancer drugs. These include b -catenin/Tcf-4 and the interaction of transcription factor activation domains with p300/CBP.
Src and focal adhesion kinase (FAK) are activated by growth factor receptors and by integrin-mediated cell adhesion. FAK signaling is critical for changes in cell morphology and migration, and thus may be an important driving force in the invasiveness of human tumors. We have determined the structure of the N-terminal FERM domain of FAK, and we are working to understand how interactions of this domain may regulate the kinase.
In T-cell activation, we are studying the Src-family kinases Lck and Fyn . We have recently determined structures of the N-terminal domain of Lck in complex with the cytoplasmic tails of T-cell co-receptors CD4 and CD8 using multi-dimensional NMR methods. Additionally, we are studying the mechanisms by which the adapter protein SAP can recruit and activate Fyn .
Formin proteins have recently been discovered to directly nucleate unbranched actin filaments found in diverse structures including stress fibers, actin cables, and the contractile ring. A conserved formin homology – 2 domain in the C-terminus of formin proteins is critical for actin assembly activity. We are studying the structure of the FH2 domain and the mechanisms by which it assembles actin filaments. Additionally, we are studying the intra- and inter-molecular interactions that modulate this activity in response to Rho-family GTPases.
Our laboratory studies the structural biology of cell signaling and the actin cytoskeleton.
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