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== Function == | == Function == | ||
[https://www.uniprot.org/uniprot/TGTP2_MOUSE TGTP2_MOUSE] Involved in innate cell-autonomous resistance to intracellular pathogens, such as Toxoplasma gondii. During avirulent type II T. gondii infection, recruited to the parasitophorous vacuole (PV) membrane, leading to PV vesiculation and rupture, and subsequent digestion of the parasite within the cytosol (PubMed:19265156, PubMed:24563254). Not recruited to virulent type I T. gondii PV membrane (PubMed:19265156). May confer an antiviral state for vesicular stomatitis virus (PubMed:9725230).<ref>PMID:19265156</ref> <ref>PMID:24563254</ref> <ref>PMID:9725230</ref> | [https://www.uniprot.org/uniprot/TGTP2_MOUSE TGTP2_MOUSE] Involved in innate cell-autonomous resistance to intracellular pathogens, such as Toxoplasma gondii. During avirulent type II T. gondii infection, recruited to the parasitophorous vacuole (PV) membrane, leading to PV vesiculation and rupture, and subsequent digestion of the parasite within the cytosol (PubMed:19265156, PubMed:24563254). Not recruited to virulent type I T. gondii PV membrane (PubMed:19265156). May confer an antiviral state for vesicular stomatitis virus (PubMed:9725230).<ref>PMID:19265156</ref> <ref>PMID:24563254</ref> <ref>PMID:9725230</ref> | ||
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== Publication Abstract from PubMed == | |||
Irgb6 is a priming immune-related GTPase (IRG) that counteracts Toxoplasma gondii. It is known to be recruited to the low virulent type II T. gondii parasitophorous vacuole (PV), initiating cell-autonomous immunity. However, the molecular mechanism by which immunity-related GTPases become inactivated after the parasite infection remains obscure. Here, we found that Thr95 of Irgb6 is prominently phosphorylated in response to low virulent type II T. gondii infection. We observed that a phosphomimetic T95D mutation in Irgb6 impaired its localization to the PV and exhibited reduced GTPase activity in vitro. Structural analysis unveiled an atypical conformation of nucleotide-free Irgb6-T95D, resulting from a conformational change in the G-domain that allosterically modified the PV membrane-binding interface. In silico docking corroborated the disruption of the physiological membrane binding site. These findings provide novel insights into a T. gondii-induced allosteric inactivation mechanism of Irgb6. | |||
Structural basis of Irgb6 inactivation by Toxoplasma gondii through the phosphorylation of switch I.,Okuma H, Saijo-Hamano Y, Yamada H, Sherif AA, Hashizaki E, Sakai N, Kato T, Imasaki T, Kikkawa S, Nitta E, Sasai M, Abe T, Sugihara F, Maniwa Y, Kosako H, Takei K, Standley DM, Yamamoto M, Nitta R Genes Cells. 2024 Jan;29(1):17-38. doi: 10.1111/gtc.13080. Epub 2023 Nov 20. PMID:37984375<ref>PMID:37984375</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
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== References == | == References == | ||
<references/> | <references/> | ||
Latest revision as of 10:36, 3 July 2024
Crystal Structure of nucleotide-free Irgb6_T95D mutantCrystal Structure of nucleotide-free Irgb6_T95D mutant
Structural highlights
FunctionTGTP2_MOUSE Involved in innate cell-autonomous resistance to intracellular pathogens, such as Toxoplasma gondii. During avirulent type II T. gondii infection, recruited to the parasitophorous vacuole (PV) membrane, leading to PV vesiculation and rupture, and subsequent digestion of the parasite within the cytosol (PubMed:19265156, PubMed:24563254). Not recruited to virulent type I T. gondii PV membrane (PubMed:19265156). May confer an antiviral state for vesicular stomatitis virus (PubMed:9725230).[1] [2] [3] Publication Abstract from PubMedIrgb6 is a priming immune-related GTPase (IRG) that counteracts Toxoplasma gondii. It is known to be recruited to the low virulent type II T. gondii parasitophorous vacuole (PV), initiating cell-autonomous immunity. However, the molecular mechanism by which immunity-related GTPases become inactivated after the parasite infection remains obscure. Here, we found that Thr95 of Irgb6 is prominently phosphorylated in response to low virulent type II T. gondii infection. We observed that a phosphomimetic T95D mutation in Irgb6 impaired its localization to the PV and exhibited reduced GTPase activity in vitro. Structural analysis unveiled an atypical conformation of nucleotide-free Irgb6-T95D, resulting from a conformational change in the G-domain that allosterically modified the PV membrane-binding interface. In silico docking corroborated the disruption of the physiological membrane binding site. These findings provide novel insights into a T. gondii-induced allosteric inactivation mechanism of Irgb6. Structural basis of Irgb6 inactivation by Toxoplasma gondii through the phosphorylation of switch I.,Okuma H, Saijo-Hamano Y, Yamada H, Sherif AA, Hashizaki E, Sakai N, Kato T, Imasaki T, Kikkawa S, Nitta E, Sasai M, Abe T, Sugihara F, Maniwa Y, Kosako H, Takei K, Standley DM, Yamamoto M, Nitta R Genes Cells. 2024 Jan;29(1):17-38. doi: 10.1111/gtc.13080. Epub 2023 Nov 20. PMID:37984375[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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