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  • 1
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    Malaria parasites target the hepatocyte receptor EphA2 for successful host infection (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-11-28
    Description: The invasion of a suitable host hepatocyte by mosquito-transmitted Plasmodium sporozoites is an essential early step in successful malaria parasite infection. Yet precisely how sporozoites target their host cell and facilitate productive infection remains largely unknown. We found that the hepatocyte EphA2 receptor was critical for establishing a permissive intracellular replication compartment, the parasitophorous vacuole. Sporozoites productively infected hepatocytes with high EphA2 expression, and the deletion of EphA2 protected mice from liver infection. Lack of host EphA2 phenocopied the lack of the sporozoite proteins P52 and P36. Our data suggest that P36 engages EphA2, which is likely to be a key step in establishing the permissive replication compartment.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kaushansky, Alexis -- Douglass, Alyse N -- Arang, Nadia -- Vigdorovich, Vladimir -- Dambrauskas, Nicholas -- Kain, Heather S -- Austin, Laura S -- Sather, D Noah -- Kappe, Stefan H I -- 1K99AI111785-01A1/AI/NIAID NIH HHS/ -- 1R01GM101183-01A1/GM/NIGMS NIH HHS/ -- K99 AI111785/AI/NIAID NIH HHS/ -- R01 GM101183/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Nov 27;350(6264):1089-92. doi: 10.1126/science.aad3318.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Infectious Disease Research (formerly Seattle Biomedical Research Institute), 307 Westlake Avenue North, No. 500, Seattle, WA 98109, USA. alexis.kaushansky@cidresearch.org stefan.kappe@cidresearch.org. ; Center for Infectious Disease Research (formerly Seattle Biomedical Research Institute), 307 Westlake Avenue North, No. 500, Seattle, WA 98109, USA. ; Center for Infectious Disease Research (formerly Seattle Biomedical Research Institute), 307 Westlake Avenue North, No. 500, Seattle, WA 98109, USA. Department of Global Health, University of Washington, Seattle, WA 98195, USA. ; Center for Infectious Disease Research (formerly Seattle Biomedical Research Institute), 307 Westlake Avenue North, No. 500, Seattle, WA 98109, USA. Department of Global Health, University of Washington, Seattle, WA 98195, USA. alexis.kaushansky@cidresearch.org stefan.kappe@cidresearch.org.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26612952" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anopheles/parasitology ; Cell Line, Tumor ; Hepatocytes/*enzymology/*parasitology ; Humans ; Malaria/*enzymology/genetics/*parasitology ; Mice ; Mice, Inbred BALB C ; Mice, Mutant Strains ; Plasmodium/genetics/*physiology ; Protozoan Proteins/*metabolism ; Receptor, EphA2/genetics/*metabolism ; Sporozoites/*physiology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 2
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    Structure of the C-terminal guanine nucleotide exchange factor module of Trio in an autoinhibited conformation reveals its oncogenic potential (2019)
    The American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2019
    Description: 〈p〉The C-terminal guanine nucleotide exchange factor (GEF) module of Trio (TrioC) transfers signals from the Gα〈sub〉q/11〈/sub〉 subfamily of heterotrimeric G proteins to the small guanosine triphosphatase (GTPase) RhoA, enabling Gα〈sub〉q/11〈/sub〉-coupled G protein–coupled receptors (GPCRs) to control downstream events, such as cell motility and gene transcription. This conserved signal transduction axis is crucial for tumor growth in uveal melanoma. Previous studies indicate that the GEF activity of the TrioC module is autoinhibited, with release of autoinhibition upon Gα〈sub〉q/11〈/sub〉 binding. Here, we determined the crystal structure of TrioC in its basal state and found that the pleckstrin homology (PH) domain interacts with the Dbl homology (DH) domain in a manner that occludes the Rho GTPase binding site, thereby suggesting the molecular basis of TrioC autoinhibition. Biochemical and biophysical assays revealed that disruption of the autoinhibited conformation destabilized and activated the TrioC module in vitro. Last, mutations in the DH-PH interface found in patients with cancer activated TrioC and, in the context of full-length Trio, led to increased abundance of guanosine triphosphate–bound RhoA (RhoA·GTP) in human cells. These mutations increase mitogenic signaling through the RhoA axis and, therefore, may represent cancer drivers operating in a Gα〈sub〉q/11〈/sub〉-independent manner.〈/p〉
    Print ISSN: 1945-0877
    Electronic ISSN: 1937-9145
    Topics: Biology , Medicine
    Published by The American Association for the Advancement of Science (AAAS)
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