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Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York 10021, USA
Reprint requests to: Diana Murray, Department of Microbiology and Immunology, Weill Medical College of Cornell University, 1300 York Avenue, Box 62, New York, NY 10021, USA; e-mail: dim2007{at}med.cornell.edu; fax: (212) 746-8587.
Phospholipases C (PLCs) reversibly associate with membranes to hydrolyze phosphatidylinositol-4, 5-bisphosphate (PI[4,5]P2) and comprise four main classes: ß, 
, 
, and 
. Most eukaryotic PLCs contain a single, N-terminal pleckstrin homology (PH) domain, which is thought to play an important role in membrane targeting. The structure of a single PLC PH domain, that from PLC1, has been determined; this PH domain binds PI(4,5)P2 with high affinity and stereospecificity and has served as a paradigm for PH domain functionality. However, experimental studies demonstrate that PH domains from different PLC classes exhibit diverse modes of membrane interaction, reflecting the dissimilarity in their amino acid sequences. To elucidate the structural basis for their differential membrane-binding specificities, we modeled the three-dimensional structures of all mammalian PLC PH domains by using bioinformatic tools and calculated their biophysical properties by using continuum electrostatic approaches. Our computational analysis accounts for a large body of experimental data, provides predictions for those PH domains with unknown functions, and indicates functional roles for regions other than the canonical lipid-binding site identified in the PLC1-PH structure. In particular, our calculations predict that (1) members from each of the four PLC classes exhibit strikingly different electrostatic profiles than those ordinarily observed for PH domains in general, (2) nonspecific electrostatic interactions contribute to the membrane localization of PLC-, PLC-, and PLCß-PH domains, and (3) phosphorylation regulates the interaction of PLCß-PH with its effectors through electrostatic repulsion. Our molecular models for PH domains from all of the PLC classes clearly demonstrate how a common structural fold can serve as a scaffold for a wide range of surface features and biophysical properties that support distinctive functional roles.
Keywords: Phospholipase C; pleckstrin homology domain; bioinformatics; continuum electrostatics; membrane association; computational biology
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