Abstract
Membrane readers take part in trafficking and signaling processes by localizing proteins to organelle surfaces and transducing molecular information. They accomplish this by engaging phosphoinositides (PIs), a class of lipid molecules which are found in different proportions in various cellular membranes. The prototypes are the PX domains, which exhibit a range of specificities for PIs. Our meta-analysis indicates that recognition of membranes by PX domains is specifically controlled by modification of lysine and arginine residues including acetylation, hydroxyisobutyrylation, glycation, malonylation, methylation and succinylation of sidechains that normally bind headgroups of phospholipids including organelle-specific PI signals. Such metabolite-modulated residues in lipid binding elements are named MET-stops here to highlight their roles as erasers of membrane reader functions. These modifications are concentrated in the membrane binding sites of half of all 49 PX domains in the human proteome and correlate with phosphoregulatory sites, as mapped using the Membrane Optimal Docking Area (MODA) algorithm. As these motifs are mutated and modified in various cancers and the responsible enzymes serve as potential drug targets, the discovery of MET-stops as a widespread inhibitory mechanism may aid in the development of diagnostics and therapeutics aimed at the readers, writers and erasers of the PI code.
Highlights
Membrane readers are protein domains that recognize unique PI lipids that mark various organelle membranes found in eukaryotic cells
All human PX domains were categorized based on their phosphoinositide phosphate (PIP) ligands using a lipid specificity index (LSI) in order to investigate possible relationships with metabolite-based post-translational modifications (PTMs) (Table 1)
The Lipid Specificity Index (LSI) values of the PX domains of SNX30 and SNX33, which have not been experimentally determined, were inferred to be similar to that of SNX7 and SNX18, respectively, as they have the most similar sequences, binding motifs and multidomain structures. This represents the best-defined and most diverse family of membrane readers in terms of PIP-binding, allowing us to explore which types of PIP interactions are likely to be affected by the various protein modifications
Summary
Membrane readers are protein domains that recognize unique PI lipids that mark various organelle membranes found in eukaryotic cells. The best understood are the FYVE, PH, and PX domain superfamilies, which represent the core of the PI code that underlies eukaryotic membrane recognition (Overduin et al, 2001; Sato et al, 2001) They comprise hundreds of domains and may only represent a small fraction of the total number of membrane readers (Overduin and Kervin, submitted), with the weak, dynamic or temperamental lipid binding activities of many proteins remaining technically difficult to detect. How they are regulated remains obscure, prompting this investigation into PI code control.
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