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- 저자 : Bowie, James U. (검색결과 11 건)
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( Nicole Pui Yu Ho ),( Bowie Lik Ling Cheng ),( Irene Oi Lin Ng ),( Terence Kin Wah Lee ) 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1
Aims: Frequent relapse and drug resistance may be attributed to the existence of tumor-initiating cells (T-ICs) in hepatocellular carcinoma (HCC). We investigated the functional role and clinical significance of Interleukin-receptor associated kinase 1 (IRAK1) in regulation of liver tumor-initiating cells (T-ICs) and sorafenib resistance, aiming to develop a novel therapeutic strategy against HCC. Methods: We evaluated the clinic-pathological relevance of IRAK1 in HCC clinical samples by qPCR and immunohistochemical analyses. Lentiviral-based overexpression and knockdown approaches were performed to characterize functional roles of IRAK1 in regulation of liver T-ICs and sorafenib resistance. Molecular pathways mediating the phenotypic alterations was identified through RNA sequencing analysis and functional rescue experiments. The combinatorial effect of IRAK1/4 inhibitor and sorafenib was tested in vivo. Results: From transcriptome sequencing, we identified IRAK1 in TLR/IRAK pathway to be significantly upregulated in HCC. IRAK1 overexpression in HCC was further confirmed at mRNA and protein levels, and correlated with larger tumor size. Interestingly, IRAK4, an upstream regulator of IRAK1, was also found to be consistently upregulated. Through lentiviral based knockdown and overexpression approaches, we demonstrated that IRAK1 regulates traits of liver T-ICs. Similar phenotypic effects were observed when HCC cells were treated with IRAK1/4 inhibitor. Through RNA sequencing analysis by comparing expression profiles between sh-IRAK1 and control cells, we identified Aldo-Keto Reductase Family 1, Member 10 (AKR1B10) as a downstream target of IRAK1. AKR1B10 was found to be overexpressed in HCC, and correlated with IRAK1 expression. Functional analysis demonstrated that knockdown of AKR1B10 offset the IRAK1 induced T-IC functions through regulating AP-1 complex. Using HCC xenograft model, we found that IRAK1/4 inhibitor in combination with sorafenib demonstrated a maximal tumor suppressive effect. Conclusions: IRAK1/AP-1/AKR1B10 signaling cascade regulates liver T-ICs and sorafenib sensitivity. Targeting IRAK1 alone or in combination with sorafenib might be a novel strategy against HCC.
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Schmidlin F.G.,Sullivan J.J.,Bowie M.H.,Read S.F.J.,Howlett B.G. 한국응용곤충학회 2021 Journal of Asia-Pacific Entomology Vol.24 No.3
On-farm native plantings support insect pollinator diversity, however, they must move between this habitat and crops grown elsewhere on the farm if they are to have any possibility of delivering pollination services that benefit growers. To determine whether pollinator movement occurs, sticky traps to capture verified crop pollinating insects (bees and non-bees species) were placed at distances of 0, 50, 100, 150 and 250 m from 5 year old native plantings into adjacent grass crops on three farms in New Zealand. These were activated twice for 48 h in Dec 2017 and Jan 2018. Captured pollinators were examined for pollen originating from the native plantings. A total of 993 individuals from 13 crop pollinating species were counted of which 506 were examined for pollen. Eight individuals representing three pollinator species were found with pollen sourced from the plantings. Of these, the native bee Lasioglossum sordidum (n = 4) was found to have travelled up to 250 m, while the native flies Melangyna novaezelandiae (n = 3) and Odontomyia sp. (n = 1) travelled up to 150 m. Despite finding few pol linators moving between these habitats, we recommend further studies to assess (1) whether the current study is truly indicative of limited pollinator movement across these habitats at broader temporal (e.g. seasonal and yearly), spatial and system scales (e.g. a broader range of agriculture systems and regions). Such knowledge can inform farmers on whether or not it is worthwhile establishing on-farm native plantings to support pollinators.
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Molecular dynamics simulation strategies for protein-micelle complexes
Cheng, X.,Kim, J.K.,Kim, Y.,Bowie, J.U.,Im, W. Elsevier Pub. Co 2016 Biochimica et biophysica acta, Biomembranes Vol.1858 No.7
The structure and stability of membrane proteins can vary widely in different detergents and this variability has great practical consequences for working with membrane proteins. Nevertheless, the mechanisms that operate to alter the behavior of proteins in micelles are poorly understood and not predictable. Atomic simulations could provide considerable insight into these mechanisms. Building protein-micelle complexes for simulation is fraught with uncertainty, however, in part because it is often unknown how many detergent molecules are present in the complex. Here, we describe several convenient ways to employ Micelle Builder in CHARMM-GUI to rapidly construct protein-micelle complexes and performed simulations of the isolated voltage-sensor domain of voltage-dependent potassium-selective channel and an antimicrobial peptide papiliocin with varying numbers of detergents. We found that once the detergent number exceeds a threshold, protein-detergent interactions change very little and remain very consistent with experimental observations. Our results provide a platform for future studies of the interplays between protein structure and detergent properties at the atomic level. This article is part of a Special Issue entitled: Membrane Proteins edited by J.C. Gumbart and Sergei Noskov.
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Nam, Hyun-Jun,Han, Seong Kyu,Bowie, James U.,Kim, Sanguk Public Library of Science 2013 PLoS computational biology Vol.9 No.3
<▼1><P>Of the membrane proteins of known structure, we found that a remarkable 67% of the water soluble domains are structurally similar to water soluble proteins of known structure. Moreover, 41% of known water soluble protein structures share a domain with an already known membrane protein structure. We also found that functional residues are frequently conserved between extramembrane domains of membrane and soluble proteins that share structural similarity. These results suggest membrane and soluble proteins readily exchange domains and their attendant functionalities. The exchanges between membrane and soluble proteins are particularly frequent in eukaryotes, indicating that this is an important mechanism for increasing functional complexity. The high level of structural overlap between the two classes of proteins provides an opportunity to employ the extensive information on soluble proteins to illuminate membrane protein structure and function, for which much less is known. To this end, we employed structure guided sequence alignment to elucidate the functions of membrane proteins in the human genome. Our results bridge the gap of fold space between membrane and water soluble proteins and provide a resource for the prediction of membrane protein function. A database of predicted structural and functional relationships for proteins in the human genome is provided at sbi.postech.ac.kr/emdmp.</P></▼1><▼2><P><B>Author Summary</B></P><P>Membrane proteins play important roles in cellular communication and molecular transport. However, experimental difficulties and lack of structural information have limited the functional characterization of membrane proteins. In this study, we find that over 60% of the extramembrane domains were structurally related to proteins of known structure. The exchanges between membrane and soluble proteins are particularly frequent in eukaryotes, indicating that this is an important mechanism for increasing functional complexity. This result has important implications for the evolution of membrane and soluble proteins. Beyond that, it provides a previously untapped resource for predicting the functions of many membrane proteins without a known function. Based on these results, we provide a new database of predicted functional and structural overlaps for all membrane proteins in the human genome.</P></▼2>
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Applications of Single-Molecule Methods to Membrane Protein Folding Studies
Jefferson, Robert E.,Min, Duyoung,Corin, Karolina,Wang, Jing Yang,Bowie, James U. Elsevier 2018 Journal of molecular biology Vol.430 No.4
<P><B>Abstract</B></P> <P>Protein folding is a fundamental life process with many implications throughout biology and medicine. Consequently, there have been enormous efforts to understand how proteins fold. Almost all of this effort has focused on water-soluble proteins, however, leaving membrane proteins largely wandering in the wilderness. The neglect has occurred not because membrane proteins are unimportant but rather because they present many theoretical and technical complications. Indeed, quantitative membrane protein folding studies are generally restricted to a handful of well-behaved proteins. Single-molecule methods may greatly alter this picture, however, because the ability to work at or near infinite dilution removes aggregation problems, one of the main technical challenges of membrane protein folding studies.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Single-molecule fluorescence applications to membrane protein folding </LI> <LI> Single-molecule fluorescence methods for measuring membrane protein oligomerization </LI> <LI> Atomic force spectroscopy of membrane protein extraction from bilayers </LI> <LI> Forced unfolding of membrane proteins using magnetic tweezers </LI> <LI> Unfolding of single membrane proteins <I>in vacuo</I> using mass spectroscopy </LI> </UL> </P> <P><B>Graphical Abstract</B></P> <P>[DISPLAY OMISSION]</P>
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Genetic selection system for improving recombinant membrane protein expression in<i>E. coli</i>
Massey-Gendel, Elizabeth,Zhao, Anni,Boulting, Gabriella,Kim, Hye-Yeon,Balamotis, Michael A.,Seligman, Len M.,Nakamoto, Robert K.,Bowie, James U. Wiley (John WileySons) 2009 Protein science Vol.18 No.2
<P>A major barrier to the physical characterization and structure determination of membrane proteins is low yield in recombinant expression. To address this problem, we have designed a selection strategy to isolate mutant strains of Escherichia coli that improve the expression of a targeted membrane protein. In this method, the coding sequence of the membrane protein of interest is fused to a C-terminal selectable marker, so that the production of the selectable marker and survival on selective media is linked to expression of the targeted membrane protein. Thus, mutant strains with improved expression properties can be directly selected. We also introduce a rapid method for curing isolated strains of the plasmids used during the selection process, in which the plasmids are removed by in vivo digestion with the homing endonuclease I-CreI. We tested this selection system on a rhomboid family protein from Mycobacterium tuberculosis (Rv1337) and were able to isolate mutants, which we call EXP strains, with up to 75-fold increased expression. The EXP strains also improve the expression of other membrane proteins that were not the target of selection, in one case roughly 90-fold.</P>
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