Abstract
The human genome encodes about 285 proteins that contain at least one annotated pleckstrin homology (PH) domain. As the first phosphoinositide binding module domain to be discovered, the PH domain recruits diverse protein architectures to cellular membranes. PH domains constitute one of the largest protein superfamilies, and have diverged to regulate many different signaling proteins and modules such as Dbl homology (DH) and Tec homology (TH) domains. The ligands of approximately 70 PH domains have been validated by binding assays and complexed structures, allowing meaningful extrapolation across the entire superfamily. Here the Membrane Optimal Docking Area (MODA) program is used at a genome-wide level to identify all membrane docking PH structures and map their lipid-binding determinants. In addition to the linear sequence motifs which are employed for phosphoinositide recognition, the three dimensional structural features that allow peripheral membrane domains to approach and insert into the bilayer are pinpointed and can be predicted ab initio. The analysis shows that conserved structural surfaces distinguish which PH domains associate with membrane from those that do not. Moreover, the results indicate that lipid-binding PH domains can be classified into different functional subgroups based on the type of membrane insertion elements they project towards the bilayer.
Highlights
The pleckstrin homology (PH) domain was discovered 22 years ago in various proteins including pleckstrin which are involved in signaling, cytoskeletal organization, membrane trafficking and phospholipid processing [1,2]
All members of the PH domain superfamily contain a conserved fold based on seven antiparallel β-strands arranged in a sandwich which is capped at its splayed corner by a C-terminal α-helix
The low conservation of the composition and length of the exposed, dynamic loops reflects the range of unique roles of the array of PH domains, and present challenges for accurately predicting their functions
Summary
The pleckstrin homology (PH) domain was discovered 22 years ago in various proteins including pleckstrin which are involved in signaling, cytoskeletal organization, membrane trafficking and phospholipid processing [1,2]. The phosphatidylinositol-4,5-bisphosphate binding function of some PH domains was soon discovered [4] This finding indicated that some PH domains are able to transiently anchor various proteins to intracellular membrane surfaces, and suggested that they could help to recruit cytosolic proteins to organelle surfaces [5]. Analysis of the available structures for these domains revealed unprecedented functional surfaces that are considered in light of the available biological and biochemical data. This analysis indicates that at least 61% of annotated PH domains associate with membranes, and present divergent features that account for their distinct specificities and affinities. The tools and data can be used to classify functional properties and consequences of deleterious mutations across the superfamily
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