Phosphoinositide Recognition Sites Are Blocked by Metabolite Attachment

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.

Characterization of the First Secreted Sorting Nexin Identified in the Leishmania Protists

“…Sequence analysis revealed a PX domain PI-binding structural module at the N-terminal half of this protein, confirming its initial classification as a phosphoinositide-binding protein [42]. PX domain-containing proteins are candidate PI effectors with roles in the PI regulatory network involved in fundamental processes for the life of eukaryotes [17,56,57], while all members of the SNX family contain at least one PX domain [2]. The LdBPK_352470 gene encodes a protein of 417 a.a. residues (predicted MW 46.6 kDa) and is registered in UniProt under the identifier A0A504X805.…”

Multifaceted membrane binding head of the SARS-CoV-2 spike protein

“… Lomize, Todd, and Pogozheva, 2022 ). The regulatory impact of small modifications is generally limited to distances corresponding to ∼5 residues, as these bounds were previously useful for identifying positions that, when phosphorylated or metabolite-modified, modulate specific membrane recognition by protein residues acting as PIP-stops ( Kervin and Overduin, 2021 ) and MET-stops majority of membrane binding ( Kervin et al, 2021 ).…”