Jon W. Lomasney, MD Assistant Professor Pathology and Molecular Pharmacology and Biological Chemistry Molecular basis for protein-lipid interaction Curricula: Pharmacology and Toxicology Structural Biology and Biochemistry E-mail:   j-lomasney@northwestern.edu

To visit the Lomasney Lab website click here

Lipids are important regulators of the activity of many proteins including those involved in cardiac, vascular, pulmonary, and neural regulation, yet little is known about the molecular mechanisms mediating these effects. My laboratory is engaged in a program of basic research to elucidate the molecular mechanisms by which lipids act as specific ligands to regulate cellular responses, and to investigate in select areas of cardiovascular disease how aberrations of signaling pathways may play a vital role in the pathogenesis of human disease.

We have used the family of phosphoinositide-specific phospholipase C (PLC) isoforms as a model to study protein-lipid interactions. Upon stimulation by various hormones these membrane associated enzymes hydrolyze polyphosphoinositides to yield second messengers such diacylglycerol and inositol 1,4,5-trisphosphate. During the past several years we have identified three structural motifs in the PLC delta 1 isoform responsible for substrate binding, catalysis, and enzyme translocation. All three motifs require the binding of a specific lipid for function. The structural motif mediating translocation also modulates the rate catalysis, and is encoded by a unique domain termed the pleckstrin homology or PH domain. This newly discovered protein module of 100 amino acids exists in many molecules (including PLC delta1) which participate in signal transduction. Our work is among the first to demonstrate a clear function in signal transduction for the PH domain, and serves a paradigm for the activation and regulation of many signaling molecules.

Work in progress includes characterization of a new family of PLC isoforms, and the elucidation of the physiological roles of various PLC isoforms using primary cell culture and transgenic mice.

Publications:

Bromann, P., Boetticher, E., and Lomasney, J.W. A single amino acid substitution in the PH domain of PLC delta 1 increases catalytic activity. J. Biol. Chem. 272; 16240-16246, 1997.

Lomasney, J.W., Cheng, H-F, Roffler, S.R. and King, K. Activation of PLC d 1, by a Ca++-Enzyme-Phosphatidylserine Ternary Complex. J. Biol. Chem. 274; 21995-22001,1999.

Murthy, S.N.P., Lomasney, J.W., Mak, E. and Lorand, L. Binding of Gh/transglutaminase to phospholipase C d 1 is regulated by GTP. Proc. Nat'l. Acad. Sci., USA 96:21; 11815-11819, 1999.