Cellular functions of phosphatidylinositol 3-phosphate and FYVE domain proteins.
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ABSTRACT:
SUBMITTER: Gillooly DJ
PROVIDER: S-EPMC1221734 | biostudies-other | 2001 Apr
REPOSITORIES: biostudies-other
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Project description:The FYVE domain is a small zinc binding module that recognizes phosphatidylinositol 3-phosphate [PtdIns(3)P], a phospholipid enriched in membranes of early endosomes and other endocytic vesicles. It is usually present as a single module or rarely as a tandem repeat in eukaryotic proteins involved in a variety of biological processes including endo- and exocytosis, membrane trafficking and phosphoinositide metabolism. A number of FYVE domain-containing proteins are recruited to endocytic membranes through the specific interaction of their FYVE domains with PtdIns(3)P. Structures and PtdIns(3)P binding modes of several FYVE domains have recently been characterized, shedding light on the molecular basis underlying multiple cellular functions of these proteins. Here, structural and functional aspects and the current mechanism of the multivalent membrane anchoring by monomeric or dimeric FYVE domain are reviewed. This mechanism involves stereospecific recognition of PtdIns(3)P that is facilitated by non-specific electrostatic contacts and modulated by the histidine switch, and is accompanied by hydrophobic insertion. Contributions of each component to the FYVE domain specificity and affinity for PtdIns(3)P-containing membranes are discussed.
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Project description:Phosphatidylinositol 3-phosphate [PtdIns(3)P], a phospholipid produced by PI 3-kinases in early endosomes and multivesicular bodies, often serves as a marker of endosomal membranes. PtdIns(3)P recruits and activates effector proteins containing the FYVE or PX domain and therefore regulates a variety of biological processes including endo- and exocytosis, membrane trafficking, protein sorting, signal transduction and cytoskeletal rearrangement. Structures and PtdIns(3)P binding modes of several FYVE and PX domains have recently been characterized, unveiling the molecular basis underlying multiple cellular functions of these proteins. Here, structural and functional aspects and current mechanisms of the multivalent membrane anchoring by the FYVE and PX domains are reviewed and compared.
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Project description:BACKGROUND: FYVE domains have emerged as membrane-targeting domains highly specific for phosphatidylinositol 3-phosphate (PtdIns(3)P). They are predominantly found in proteins involved in various trafficking pathways. Although FYVE domains may function as individual modules, dimers or in partnership with other proteins, structurally, all FYVE domains share a fold comprising two small characteristic double-stranded beta-sheets, and a C-terminal alpha-helix, which houses eight conserved Zn2+ ion-binding cysteines. To date, the structural, biochemical, and biophysical mechanisms for subcellular targeting of FYVE domains for proteins from various model organisms have been worked out but plant FYVE domains remain noticeably under-investigated. RESULTS: We carried out an extensive examination of all Arabidopsis FYVE domains, including their identification, classification, molecular modeling and biophysical characterization using computational approaches. Our classification of fifteen Arabidopsis FYVE proteins at the outset reveals unique domain architectures for FYVE containing proteins, which are not paralleled in other organisms. Detailed sequence analysis and biophysical characterization of the structural models are used to predict membrane interaction mechanisms previously described for other FYVE domains and their subtle variations as well as novel mechanisms that seem to be specific to plants. CONCLUSIONS: Our study contributes to the understanding of the molecular basis of FYVE-based membrane targeting in plants on a genomic scale. The results show that FYVE domain containing proteins in plants have evolved to incorporate significant differences from those in other organisms implying that they play a unique role in plant signaling pathways and/or play similar/parallel roles in signaling to other organisms but use different protein players/signaling mechanisms.
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Project description:BACKGROUND: Phosphatidylinositol 3-phosphate is involved in regulation of several key cellular processes, mainly endocytosis, signaling, nuclear processes, cytoskeletal remodelling, cell survival, membrane trafficking, phagosome maturation and autophagy. In most cases effector proteins bind to this lipid, using either FYVE or PX domain. These two domains are distributed amongst varied life forms such as virus, protists, fungi, viridiplantae and metazoa. As the binding ligand is identical for both domains, the goal of this study was to understand if there is any selectivity for either of these domains in different taxa. Further, to understand the different cellular functions that these domains may be involved in, we analyzed the taxonomic distribution of additional domains that associate with FYVE and PX. RESULTS: There is selectivity for either FYVE or PX in individual genomes where both domains are present. Fungi and metazoa encode more PX, whereas streptophytes in viridiplantae encode more FYVE. Excess of FYVE in streptophytes results from proteins containing RCC1and DZC domains and FYVE domains in these proteins have a non-canonical ligand-binding site. Within a taxonomic group the selected domain associates with a higher number of other domains and is thus expected to discharge a larger number of cellular functions. Also, while certain associated domains are present in all taxonomic groups, most of them are unique to a specific group indicating that while certain common functions are discharged by these domains in all taxonomic groups, some functions appear to be group specific. CONCLUSIONS: Although both FYVE and PX bind to PtdIns(3)P, genomes of different taxa show distinct selectivity of encoding either of the two. Higher numbers of taxonomic group specific domains co-occur with the more abundant domain (FYVE/PX) indicating that group-specific rare domain architectures might have emerged to accomplish certain group-specific functions.
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Project description:Professional phagocytic cells ingest microbial intruders by engulfing them into phagosomes, which subsequently mature into microbicidal phagolysosomes. Phagosome maturation requires sequential fusion of the phagosome with early endosomes, late endosomes, and lysosomes. Although various phosphoinositides (PIPs) have been detected on phagosomes, it remained unclear which PIPs actually govern phagosome maturation. Here, we analyzed the involvement of PIPs in fusion of phagosomes with various endocytic compartments and identified phosphatidylinositol 4-phosphate [PI(4)P], phosphatidylinositol 3-phosphate [PI(3)P], and the lipid kinases that generate these PIPs, as mediators of phagosome-lysosome fusion. Phagosome-early endosome fusion required PI(3)P, yet did not depend on PI(4)P. Thus, PI(3)P regulates phagosome maturation at early and late stages, whereas PI(4)P is selectively required late in the pathway.
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Project description:While the majority of phosphatidylinositol-4, 5-bisphosphate (PI-4, 5-P2) in mammalian cells is generated by the conversion of phosphatidylinositol-4-phosphate (PI-4-P) to PI-4, 5-P2, a small fraction can be made by phosphorylating phosphatidylinositol-5-phosphate (PI-5-P). The physiological relevance of this second pathway is not clear. Here, we show that deletion of the genes encoding the two most active enzymes in this pathway, Pip4k2a and Pip4k2b, in the liver of mice causes a large enrichment in lipid droplets and in autophagic vesicles during fasting. These changes are due to a defect in the clearance of autophagosomes that halts autophagy and reduces the supply of nutrients salvaged through this pathway. Similar defects in autophagy are seen in nutrient-starved Pip4k2a-/-Pip4k2b-/- mouse embryonic fibroblasts and in C. elegans lacking the PI5P4K ortholog. These results suggest that this alternative pathway for PI-4, 5-P2 synthesis evolved, in part, to enhance the ability of multicellular organisms to survive starvation.
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Project description:Understanding the energetics of peripheral protein-membrane interactions is important to many areas of biophysical chemistry and cell biology. Estimating free-energy landscapes by molecular dynamics (MD) simulation is challenging for such systems, especially when membrane recognition involves complex lipids, e.g., phosphatidylinositol phosphates (PIPs). We combined coarse-grained MD simulations with umbrella sampling to quantify the binding of the well-explored GRP1 pleckstrin homology (PH) domain to model membranes containing PIP molecules. The experimentally observed preference of GRP1-PH for PIP3 over PIP2 was reproduced. Mutation of a key residue (K273A) within the canonical PIP-binding site significantly reduced the free energy of PIP binding. The presence of a noncanonical PIP-interaction site, observed experimentally in other PH domains but not previously in GRP1-PH, was also revealed. These studies demonstrate how combining coarse-grained simulations and umbrella sampling can unmask the molecular basis of the energetics of interactions between peripheral membrane proteins and complex cellular membranes.
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