TTR-52 is a secreted transthyretin-like protein of C. elegans that bridges apoptotic cells to engulfing cells. It is made in and secreted from the endoderm and clusters around apoptotic cells. There it binds surface-exposed phosphatidylserine (PS) on the dying cell and the N-terminal EMI domain of the engulfment receptor CED-1 on the engulfing cell. Its crystal structure shows an open beta-barrel resembling a C2 domain, and it forms dimers that are needed for function in vivo. TTR-52 acts in the CED-1/CED-6/CED-7 pathway and is needed for CED-1 to cluster around corpses. With CED-7 and the lipid-binding protein NRF-5, it also takes part in the release of PS-containing extracellular vesicles from apoptotic cells and in PS appearance on engulfing cells.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001786 phosphatidylserine binding | IDA PMID:20526330 Caenorhabditis elegans transthyretin-like protein TTR-52 med... | ACCEPT | Summary: Phosphatidylserine binding in vitro and on apoptotic cells in vivo (Wang et al. 2010). Reason: Core activity. TTR-52 binds PS in vitro and recognizes surface-exposed PS on apoptotic cells in vivo. Supporting Evidence: PMID:20526330 TTR-52 recognizes surface-exposed phosphatidylserine (PtdSer) in vivo and binds to both PtdSer and the extracellular domain of CED-1 in vitro |
| GO:0001786 phosphatidylserine binding | IDA PMID:22713871 Structural study of TTR-52 reveals the mechanism by which a ... | ACCEPT | Summary: Phosphatidylserine binding, with a structural model of the binding mode (Kang et al. 2012). Reason: The crystal structure study supports PS binding and proposes an ion-mediated binding mode. Supporting Evidence: PMID:22713871 TTR-52 is proposed to bind PtdSer via an "ion-mediating" PtdSer-binding mode |
| GO:0005124 scavenger receptor binding | IPI PMID:20526330 Caenorhabditis elegans transthyretin-like protein TTR-52 med... | ACCEPT | Summary: Binds the extracellular domain of the scavenger receptor CED-1 (Wang et al. 2010). Reason: Core activity. The receptor-binding half of the bridge: TTR-52 binds the CED-1 extracellular domain in vitro. Supporting Evidence: PMID:20526330 TTR-52 recognizes surface-exposed phosphatidylserine (PtdSer) in vivo and binds to both PtdSer and the extracellular domain of CED-1 in vitro |
| GO:0005124 scavenger receptor binding | IPI PMID:22713871 Structural study of TTR-52 reveals the mechanism by which a ... | ACCEPT | Summary: Binds the CED-1 EMI domain through its hydrophobic C terminus (Kang et al. 2012). Reason: Maps the binding interface on both partners. Supporting Evidence: PMID:22713871 CED-1 binds TTR-52 through its N-terminal EMI domain and that the hydrophobic region of the TTR-52 C terminus is involved in this interaction |
| GO:0005515 protein binding | IPI PMID:22727700 C. elegans secreted lipid-binding protein NRF-5 mediates PS ... | REMOVE | Summary: Protein binding with NRF-5 (Zhang et al. 2012). Reason: The association with the secreted lipid-transfer protein NRF-5 is reported and is not disputed; removal does not mean the interaction is false. Protein binding carries no functional information, and the abstract-only record supports no more informative molecular function for this interaction. The functional content (PS transfer with NRF-5 and CED-7) is captured by the aminophospholipid transport row. Supporting Evidence: PMID:22727700 NRF-5 associates with TTR-52, binds PS, and displays lipid transfer activity in vitro PMID:22727700 NRF-5 may act with CED-7 and TTR-52 to mediate PS transfer from apoptotic cells to engulfing cells |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | ACCEPT | Summary: Extracellular region, from the UniProt subcellular location (secreted). Reason: TTR-52 is secreted from the endoderm and acts extracellularly. Supporting Evidence: PMID:20526330 The TTR-52 protein is expressed in, and secreted from, C. elegans endoderm and clusters around apoptotic cells |
| GO:0009986 cell surface | IDA PMID:20526330 Caenorhabditis elegans transthyretin-like protein TTR-52 med... | ACCEPT | Summary: Cell surface; TTR-52 clusters around apoptotic cells (Wang et al. 2010). Reason: Secreted TTR-52 accumulates on the surface of apoptotic cells, where it binds exposed PS. Supporting Evidence: PMID:20526330 The TTR-52 protein is expressed in, and secreted from, C. elegans endoderm and clusters around apoptotic cells |
| GO:0009986 cell surface | IEA GO_REF:0000120 | ACCEPT | Summary: Cell surface, from InterPro and UniProt subcellular location. Reason: Agrees with the experimental cell surface annotation. Supporting Evidence: PMID:20526330 The TTR-52 protein is expressed in, and secreted from, C. elegans endoderm and clusters around apoptotic cells |
| GO:0015917 aminophospholipid transport | IMP PMID:22727702 CED-1, CED-7, and TTR-52 regulate surface phosphatidylserine... | KEEP AS NON CORE | Summary: Aminophospholipid transport; loss of TTR-52 blocks loss of exposed PS from corpses and its appearance on engulfing cells (Mapes et al. 2012). Reason: The genetic result is solid: in ttr-52 mutants PS persists on unengulfed corpses, engulfing cells fail to acquire it, and extracellular PS vesicles are reduced. The authors frame TTR-52 as a possible extracellular PS acceptor or carrier with "may", so the mechanism is not established. Kept as a non-core role alongside the bridging function. Supporting Evidence: PMID:22727702 CED-7 and TTR-52 may promote the efflux of PS from apoptotic cells through the generation of extracellular PS vesicles PMID:22727702 indicating that PS-binding TTR-52 also associates with extracellular PS vesicles and may participate in the generation of these PS vesicles |
| GO:0030674 protein-macromolecule adaptor activity | IPI PMID:20526330 Caenorhabditis elegans transthyretin-like protein TTR-52 med... | ACCEPT | Summary: Protein-macromolecule adaptor activity: bridges exposed PS on apoptotic cells to the CED-1 receptor (Wang et al. 2010). Reason: Core molecular function. TTR-52 is a bridging molecule that crosslinks the PS eat-me signal to CED-1. This adaptor term captures the bridging better than either binding term alone. Supporting Evidence: PMID:20526330 mediates recognition of apoptotic cells by crosslinking the PtdSer 'eat me' signal with the phagocyte receptor CED-1 PMID:20526330 TTR-52 recognizes surface-exposed phosphatidylserine (PtdSer) in vivo and binds to both PtdSer and the extracellular domain of CED-1 in vitro |
| GO:0043654 recognition of apoptotic cell | IDA PMID:20526330 Caenorhabditis elegans transthyretin-like protein TTR-52 med... | ACCEPT | Summary: Recognition of apoptotic cell (Wang et al. 2010). Reason: Core process. TTR-52 does part of the recognition step itself: it binds the PS signal on the corpse and presents it to CED-1, and it is needed for CED-1 clustering. Supporting Evidence: PMID:20526330 mediates recognition of apoptotic cells by crosslinking the PtdSer 'eat me' signal with the phagocyte receptor CED-1 PMID:20526330 TTR-52 acts in the cell corpse engulfment pathway mediated by CED-1, CED-6 and CED-7 and affects clustering of the phagocyte receptor CED-1 around apoptotic cells |
| GO:1902742 apoptotic process involved in development | IGI PMID:24225442 Caspase-mediated activation of Caenorhabditis elegans CED-8 ... | REMOVE | Summary: Apoptotic process involved in development (IGI with ced-8, Chen et al. 2013). Reason: In the full text, ttr-52(tm2078) is one of several engulfment-defective backgrounds used to test whether ced-8 acts through the CED-1 engulfment pathway; the conclusion concerns phagocytosis, not apoptosis. Unlike ced-1, ced-6 and ced-7, there is no evidence that ttr-52 promotes the death of weakly signalled cells (it was identified after those studies), so the positive regulation replacement used for those genes does not apply. TTR-52 acts in the corpse-recognition step, outside the dying cell's apoptotic program. Supporting Evidence: PMID:24225442 only mildly enhanced the corpse engulfment defect of the ced-1, ced-6, ced-7 or ttr-52 mutants at the L1 larval stage PMID:24225442 mainly act through the ced-1, ced-6, ced-7 and ttr-52 engulfment pathway to promote phagocytosis |
| GO:1902742 apoptotic process involved in development | IMP PMID:24225442 Caspase-mediated activation of Caenorhabditis elegans CED-8 ... | REMOVE | Summary: Apoptotic process involved in development (Chen et al. 2013). Reason: Same as the IGI row: ttr-52 is used in this paper only as a clearance-defective background, and nothing supports a role for TTR-52 in apoptosis itself. Supporting Evidence: PMID:24225442 only mildly enhanced the corpse engulfment defect of the ced-1, ced-6, ced-7 or ttr-52 mutants at the L1 larval stage PMID:24225442 mainly act through the ced-1, ced-6, ced-7 and ttr-52 engulfment pathway to promote phagocytosis |
| GO:1903561 extracellular vesicle | IDA PMID:22727702 CED-1, CED-7, and TTR-52 regulate surface phosphatidylserine... | ACCEPT | Summary: Extracellular vesicle; immuno-EM finds TTR-52 on extracellular PS vesicles near apoptotic cells (Mapes et al. 2012). Reason: Direct localization by immuno-EM. It fits the role of TTR-52 as an extracellular PS-binding protein. Supporting Evidence: PMID:22727702 indicating that PS-binding TTR-52 also associates with extracellular PS vesicles and may participate in the generation of these PS vesicles |
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Download this section (compressed HTML)Q: Does TTR-52 carry PS between membranes (as an acceptor or carrier, possibly with NRF-5), or does it only bind PS-bearing vesicles?
Q: Does TTR-52, like CED-1, CED-6 and CED-7, contribute to engulfing cells promoting the death of weakly signalled cells?
Experiment: In a weak ced-3 or ced-4 partial loss-of-function background, compare survival of specific cells such as the extra pharyngeal cells in ttr-52 mutants versus ced-1 mutants, scored with cell-type reporters.
Hypothesis: TTR-52 promotes the death of cells receiving weak death signals, as other CED-1 pathway genes do.
Type: genetic
ttr-52 encodes a transthyretin-like secreted protein that is required for proper cell corpse engulfment; genetic analysis indicates that ttr-52 functions in the ced-1/CD91 pathway for engulfment; TTR-52 binds to both surface-exposed phosphatidylserine in vivo and the extracellular domain of CED-1, therefore acting like a bridging molecule during the recognition of apoptotic cells during cell corpse engulfment; ttr-52 is expressed in, and secreted from intestinal cells and co-localizes to apoptotic cells together with CED-1.
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