Dataset Information

Distinct recognition of complement iC3b by integrins ?X?2 and ?M?2.

ABSTRACT: Recognition by the leukocyte integrins ?X?2 and ?M?2 of complement iC3b-opsonized targets is essential for effector functions including phagocytosis. The integrin-binding sites on iC3b remain incompletely characterized. Here, we describe negative-stain electron microscopy and biochemical studies of ?X?2 and ?M?2 in complex with iC3b. Despite high homology, the two integrins bind iC3b at multiple distinct sites. ?X?2 uses the ?X ?I domain to bind iC3b on its C3c moiety at one of two sites: a major site at the interface between macroglobulin (MG) 3 and MG4 domains, and a less frequently used site near the C345C domain. In contrast, ?M?2 uses its ?I domain to bind iC3b at the thioester domain and simultaneously interacts through a region near the ?M ?-propeller and ?2 ?I domain with a region of the C3c moiety near the C345C domain. Remarkably, there is no overlap between the primary binding site of ?X?2 and the binding site of ?M?2 on iC3b. Distinctive binding sites on iC3b by integrins ?X?2 and ?M?2 may be biologically beneficial for leukocytes to more efficiently capture opsonized pathogens and to avoid subversion by pathogen factors.

SUBMITTER: Xu S

PROVIDER: S-EPMC5380021 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Distinct recognition of complement iC3b by integrins αXβ2 and αMβ2.

Xu Shutong S Wang Jianchuan J Wang Jia-Huai JH Springer Timothy A TA

Proceedings of the National Academy of Sciences of the United States of America 20170314 13

Recognition by the leukocyte integrins αXβ2 and αMβ2 of complement iC3b-opsonized targets is essential for effector functions including phagocytosis. The integrin-binding sites on iC3b remain incompletely characterized. Here, we describe negative-stain electron microscopy and biochemical studies of αXβ2 and αMβ2 in complex with iC3b. Despite high homology, the two integrins bind iC3b at multiple distinct site ...[more]

PMID: 28292891

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Project description:We previously reported 18FPRGD2 uptake by the coxofemoral lining, intervertebral discs and facet joint osteophytes in OA using PET/SCAN imaging. However, the molecular mechanism by which the PRGD2 tracer interacts with joint tissues and osteophytes in OA remains unclear. As PRGD2 ligands are expected to belong to the RGD-specific integrin family, the purpose of this study was (i) to determine which integrin complexes display the highest affinity for PRGD2-based ligands, (ii) to analyze integrin expression in relevant tissues, and (iii) to test integrin regulation in chondrocytes using OA-related stimuli to increase the levels of fibrosis and ossification markers. To this end, the affinity of PRGD2-based ligands for five heterodimeric integrins was measured by competition with 125I-echistatin. In situ analyses were performed in human normal vs. OA cartilage and spinal osteophytes. Osteophytes were characterized by (immuno-)histological staining. Integrin subunit expression was tested in chondrocytes undergoing dedifferentiation, osteogenic differentiation, and inflammatory stimulation. The integrins αVβ5, αVβ3, and αVβ6 presented the highest affinity for PRGD2-based ligands. In situ, the expression of these integrins was significantly increased in OA compared to normal cartilage. Within osteophytes, the mean integrin expression score was significantly higher in blood vessels, fibrous areas, and cells from the bone lining than in osteocytes and cartilaginous zones. In vitro, the levels of integrin subunits were significantly increased during chondrocyte dedifferentiation (except for β6), fibrosis, and osteogenic differentiation as well as under inflammatory stimuli. In conclusion, anatomical zones (such as OA cartilage, intervertebral discs, and facet joint osteophytes) previously reported to show PRGD2 ligand uptake in vivo expressed increased levels of αVβ5, αVβ3, and β6 integrins, whose subunits are modulated in vitro by OA-associated conditions that increase fibrosis, inflammation, and osteogenic differentiation. These results suggest that the increased levels of integrins in OA compared to normal tissues favor PRGD2 uptake and might explain the molecular mechanism of OA imaging using the PRGD2-based ligand PET/CT.

Dataset Information

Distinct recognition of complement iC3b by integrins ?X?2 and ?M?2.

Publications

Distinct recognition of complement iC3b by integrins α<sub>X</sub>β<sub>2</sub> and α<sub>M</sub>β<sub>2</sub>.

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