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PMID:22713871

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Citation

Kang, Y, Zhao, D, Liang, H, Liu, B, Zhang, Y, Liu, Q, Wang, X and Liu, Y (2012) Structural study of TTR-52 reveals the mechanism by which a bridging molecule mediates apoptotic cell engulfment. Genes Dev. 26:1339-50

Abstract

During apoptosis, apoptotic cells are removed by professional phagocytes or neighboring engulfing cells either directly through phagocytic receptors or indirectly through bridging molecules that cross-link dying cells to phagocytes. However, how bridging molecules recognize "eat me" signals and phagocytic receptors to mediate engulfment remains unclear. Here, we report the structural and functional studies of Caenorhabditis elegans TTR-52, a recently identified bridging molecule that cross-links surface-exposed phosphatidylserine (PtdSer) on apoptotic cells to the CED-1 receptor on phagocytes. Crystal structure studies show that TTR-52 has an open β-barrel-like structure with some similarities to the PKCα-C2 domain. TTR-52 is proposed to bind PtdSer via an "ion-mediating" PtdSer-binding mode. Intensive functional studies show that 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. In addition, unlike other PtdSer-binding domains, TTR-52 forms dimers, and its dimerization is important for its function in vivo. Our results reveal the first full-length structure of a bridging molecule and the mechanism underlying bridging molecule-mediated apoptotic cell recognition.

Links

PubMed PMC3387661 Online version:10.1101/gad.187815.112

Keywords

Animals; Animals, Genetically Modified; Apoptosis; Binding Sites; Caenorhabditis elegans/cytology; Caenorhabditis elegans/metabolism; Caenorhabditis elegans Proteins/chemistry; Caenorhabditis elegans Proteins/metabolism; Green Fluorescent Proteins/metabolism; Membrane Proteins/metabolism; Models, Molecular; Mutant Proteins/chemistry; Mutant Proteins/metabolism; Mutation/genetics; Phagocytosis; Phosphatidylserines/metabolism; Prealbumin/metabolism; Protein Binding; Protein Multimerization; Recombinant Fusion Proteins/metabolism; Structure-Activity Relationship

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

CAEEL:TTR52

enables

GO:0005124: scavenger receptor binding

ECO:0000353: physical interaction evidence used in manual assertion

WB:WBGene00000415

F

Seeded From UniProt

complete

CAEEL:TTR52

enables

GO:0001786: phosphatidylserine binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

CAEEL:TTR52

enables

GO:0042803: protein homodimerization activity

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:G5ED35

F

Seeded From UniProt

complete

CAEEL:CED1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

WB:WBGene00008719

F

Seeded From UniProt

complete


See also

References

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