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  • 1
    Online Resource
    Online Resource
    DOCK2 is involved in the host genetics and biology of severe COVID-19
    Springer Science and Business Media LLC ; 2022
    In:  Nature Vol. 609, No. 7928 ( 2022-09-22), p. 754-760
    Details
    In: Nature, Springer Science and Business Media LLC, Vol. 609, No. 7928 ( 2022-09-22), p. 754-760
    Abstract: Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge 1–5 . Here we conducted a genome-wide association study (GWAS) involving 2,393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3,289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene ( DOCK2 ), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis ( n  = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target.
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
    URL: Article
    DOI: 10.1038/s41586-022-05163-5
    RVK:
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    RVK:
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    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
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  • 2
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    Online Resource
    Integration of Shaker-type K + channel, KAT1, into the endoplasmic reticulum membrane: Synergistic insertion of voltage-sensing segments, S3–S4, and independent insertion of pore-forming segments, S5–P–S6
    Proceedings of the National Academy of Sciences ; 2002
    In:  Proceedings of the National Academy of Sciences Vol. 99, No. 1 ( 2002-01-08), p. 60-65
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 99, No. 1 ( 2002-01-08), p. 60-65
    Abstract: KAT1 is a member of the Shaker family of voltage-dependent K + channels, which has six transmembrane segments (called S1–S6), including an amphipathic S4 with several positively charged residues and a hydrophobic pore-forming region (called P) between S5 and S6. In this study, we systematically evaluated the function of individual and combined transmembrane segments of KAT1 to direct the final topology in the endoplasmic reticulum membrane by in vitro translation and translocation experiments. The assay with single-transmembrane constructs showed that S1 possesses the type II signal-anchor function, whereas S2 has the stop-transfer function. The properties fit well with the results derived from combined insertion of S1 and S2. S3 and S4 failed to integrate into the membrane by themselves. The inserted glycosylation sequence at the S3–S4 loop neither prevented the translocation of S3 and S4 nor impaired the function of voltage-dependent K + transport regardless of the changed length of the S3–S4 loop. S3 and S4 are likely to be posttranslationally integrated into the membrane only when somewhat specific interaction occurs between them. S5 had the ability of translocation reinitiation, and S6 had a strong preference for N exo /C cyt orientation. The pore region resided outside because of its lack of its transmembrane-spanning property. According to their own topogenic function, combined constructs of S5–P–S6 conferred the membrane-pore-membrane topology. This finding supports the notion that a set of S5–P–S6 can be independently integrated into the membrane. The results in this study provide the fundamental topogenesis mechanism of transmembrane segments involving voltage sensor and pore region in KAT1.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.012399799
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2002
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    SSG: 11
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  • 3
    Online Resource
    Online Resource
    Evidence in support of a four transmembrane-pore-transmembrane topology model for the Arabidopsis thaliana Na + /K + translocating AtHKT1 protein, a member of the superfamily of K + transporters
    Proceedings of the National Academy of Sciences ; 2001
    In:  Proceedings of the National Academy of Sciences Vol. 98, No. 11 ( 2001-05-22), p. 6488-6493
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 98, No. 11 ( 2001-05-22), p. 6488-6493
    Abstract: The Arabidopsis thaliana AtHKT1 protein, a Na + /K + transporter, is capable of mediating inward Na + currents in Xenopus laevis oocytes and K + uptake in Escherichia coli . HKT1 proteins are members of a superfamily of K + transporters. These proteins have been proposed to contain eight transmembrane segments and four pore-forming regions arranged in a mode similar to that of a K + channel tetramer. However, computer analysis of the AtHKT1 sequence identified eleven potential transmembrane segments. We have investigated the membrane topology of AtHKT1 with three different techniques. First, a gene fusion alkaline phosphatase study in E. coli clearly defined the topology of the N-terminal and middle region of AtHKT1, but the model for membrane folding of the C-terminal region had to be refined. Second, with a reticulocyte-lysate supplemented with dog-pancreas microsomes, we demonstrated that N -glycosylation occurs at position 429 of AtHKT1. An engineered unglycosylated protein variant, N429Q, mediated Na + currents in X. laevis oocytes with the same characteristics as the wild-type protein, indicating that N -glycosylation is not essential for the functional expression and membrane targeting of AtHKT1. Five potential glycosylation sites were introduced into the N429Q. Their pattern of glycosylation supported the model based on the E. coli -alkaline phosphatase data. Third, immunocytochemical experiments with FLAG-tagged AtHKT1 in HEK293 cells revealed that the N and C termini of AtHKT1, and the regions containing residues 135–142 and 377–384, face the cytosol, whereas the region of residues 55–62 is exposed to the outside. Taken together, our results show that AtHKT1 contains eight transmembrane-spanning segments.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.101556598
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2001
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    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Location Call Number Limitation Availability
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