The cryo-EM structure of the acid activatable pore-forming immune effector Macrophage-expressed gene 1

Pang, Siew Siew; Bayly-Jones, Charles; Radjainia, Mazdak; Spicer, Bradley A.; Law, Ruby H. P.; Hodel, Adrian W; Parsons, Edward S.; Ekkel, Susan M.; Conroy, Paul J.; Ramm, Georg; Venugopal, Hariprasad; Bird, Phillip I.; Hoogenboom, Bart W.; Voskoboinik, Ilia; Gambin, Yann; Sierecki, Emma; Dunstone, Michelle Anne; Whisstock, James C.

doi:10.1038/s41467-019-12279-2

Cited by 68 publications

(145 citation statements)

References 59 publications

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“…7d, e ). Several immune response genes (e.g., Mpeg1 , a macrophage-specific marker 48 , and Clec7a , involved in the innate immune response 49 ) were upregulated in both the cerebellum and spinal cord of Matr3 S85C/S85C mice compared to Matr3 +/+ mice (Fig. 7a, b and Supplementary Data 5 ), suggesting that neuroinflammation could contribute to disease pathogenesis.…”

Section: Resultsmentioning

confidence: 99%

Selective neuronal degeneration in MATR3 S85C knock-in mouse model of early-stage ALS

et al. 2020

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A missense mutation, S85C, in the MATR3 gene is a genetic cause for amyotrophic lateral sclerosis (ALS). It is unclear how the S85C mutation affects MATR3 function and contributes to disease. Here, we develop a mouse model that harbors the S85C mutation in the endogenous Matr3 locus using the CRISPR/Cas9 system. MATR3 S85C knock-in mice recapitulate behavioral and neuropathological features of early-stage ALS including motor impairment, muscle atrophy, neuromuscular junction defects, Purkinje cell degeneration and neuroinflammation in the cerebellum and spinal cord. Our neuropathology data reveals a loss of MATR3 S85C protein in the cell bodies of Purkinje cells and motor neurons, suggesting that a decrease in functional MATR3 levels or loss of MATR3 function contributes to neuronal defects. Our findings demonstrate that the MATR3 S85C mouse model mimics aspects of early-stage ALS and would be a promising tool for future basic and preclinical research.

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Section: Resultsmentioning

confidence: 99%

Selective neuronal degeneration in MATR3 S85C knock-in mouse model of early-stage ALS

et al. 2020

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“…The ‘experimental’ reference profile was generated based on the electron density map of the MPEG-1 protein bound to a lipidic vesicle (EMD-20622) (Pang et al, 2019). The electron density corresponding to the protein was selected and subtracted in Chimera using the structure of MPEG-1 (PDBID 6U2W).…”

Section: Methodsmentioning

confidence: 99%

Cryo-EM structures and functional properties of CALHM channels of the human placenta

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Sawicka

Bahamonde-Santos

et al. 2020

Preprint

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AbstractThe transport of substances across the placenta is essential for the development of the fetus. Here, we were interested in the role of channels of the calcium homeostasis modulator (CALHM) family in the human placenta. By transcript analysis, we found the paralogs CALHM2, 4, and 6 to be highly expressed in this organ and upregulated during trophoblast differentiation. Based on electrophysiology, we found that activation of these paralogs differs from the voltage- and calcium-gated channel CALHM1. Cryo-EM structures of CALHM4 display decameric and undecameric assemblies with large cylindrical pore, while in CALHM6 a conformational change has converted the pore shape into a conus that narrows at the intracellular side, thus describing distinct functional states of the channel. The pore geometry alters the distribution of lipids, which occupy the cylindrical pore of CALHM4 in a bilayer-like arrangement whereas they have redistributed in the conical pore of CALHM6 with potential functional consequences.

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“…The Perforin-2 cytosolic tail directs the endosomes to bacteria-encapsulating phagosomes (46). Acidification of the phagosome stimulates reconfiguration of the MACPF domain, resulting in pore formation on the bacterial cell membrane (46,47). Our group was the first to demonstrate the essential role of Perforin-2 in eliminating intracellular bacterial infections (48,49), confirming the importance of this protein as an antimicrobial effector protein expressed by both phagocytic and tissue forming cells.…”

Section: Overview Of the Perforinsmentioning

confidence: 52%

“…Location in the cell Intracellular cytolytic granules (39) Membranes of intracellular endosomes (46,47) Function in GD T cells Lysis of transformed or infected cells (39)(40)(41) Destruction of intracellular bacteria (46,47) Stimulatory factors Surface receptors: -GD TCR 53 suffering from these illnesses. Compounds identified as Perforin inhibitors in NK and AB T cells include diarylthiophenes and benzenesulfonamide based therapeutics (83)(84)(85).…”

Section: Perforinmentioning

confidence: 99%

Perforins Expression by Cutaneous Gamma Delta T Cells

et al. 2020

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Gamma delta (GD) T cells are an unconventional T cell type present in both the epidermis and the dermis of human skin. They are critical to regulating skin inflammation, wound healing, and anti-microbial defense. Similar to CD8+ cytotoxic T cells expressing an alpha beta (AB) TCR, GD T cells have cytolytic capabilities. They play an important role in elimination of cutaneous tumors and virally infected cells and have also been implicated in pathogenicity of several autoimmune diseases. T cell cytotoxicity is associated with the expression of the pore forming protein Perforin. Perforin is an innate immune protein containing a membrane attack complex perforin-like (MACPF) domain and functions by forming pores in the membranes of target cells, which allow granzymes and reactive oxygen species to enter the cells and destroy them. Perforin-2, encoded by the gene MPEG1, is a newly discovered member of this protein family that is critical for clearance of intracellular bacteria. Cutaneous GD T cells express both Perforin and Perforin-2, but many questions remain regarding the role that these proteins play in GD T cell mediated cytotoxicity against tumors and bacterial pathogens. Here, we review what is known about Perforin expression by skin GD T cells and the mechanisms that contribute to Perforin activation.

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The cryo-EM structure of the acid activatable pore-forming immune effector Macrophage-expressed gene 1

Cited by 68 publications

References 59 publications

Selective neuronal degeneration in MATR3 S85C knock-in mouse model of early-stage ALS

Selective neuronal degeneration in MATR3 S85C knock-in mouse model of early-stage ALS

Cryo-EM structures and functional properties of CALHM channels of the human placenta

Perforins Expression by Cutaneous Gamma Delta T Cells

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