|Protein Science (2003) 12:1934-53|
|Northeast Structural Genomics Consortium|
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Phospholipases C (PLCs) reversibly associate with membranes to hydrolyze phosphatidylinositol-4, 5-bisphosphate (PI[4,5]P(2)) and comprise four main classes: beta, gamma, delta, and epsilon. ...
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 PLCdelta1, has been determined; this PH domain binds PI(4,5)P(2) 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 PLCdelta1-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 PLCdelta-, PLCgamma-, and PLCbeta-PH domains, and (3). phosphorylation regulates the interaction of PLCbeta-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.
|chemistry metabolism |
|Type C Phospholipases Protein Structure, Tertiary Protein Conformation Phosphorylation Lipids Phosphoproteins Phosphoinositide Phospholipase C Protein Folding Binding Sites Amino Acid Sequence Cell Membrane Sequence Homology, Amino Acid Blood Proteins Models, Molecular Phospholipase C delta Thermodynamics Humans Isoenzymes Molecular Sequence Data Sensitivity and Specificity Animals Software Protein Binding Static Electricity Hydrogen-Ion Concentration |
|51 (Last update: 03/18/2017 12:15:29pm)|
|Protein Sci. 2003 Sep;12(9):1934-53.|