ALBERT

Description: Genome-wide association studies (GWAS) have revealed genetic determinants of iron metabolism, but correlation of these with clinical phenotypes is pending. Homozygosity for HFE C282Y is the predominant genetic risk factor for hereditary hemochromatosis (HH) and may cause liver cirrhosis. However, this genotype has a low penetrance. Thus, detection of yet unknown genetic markers that identify patients at risk of developing severe liver disease is necessary for better prevention. Genetic loci associated with iron metabolism ( TF , TMPRSS6 , PCSK7 , TFR2 and Chr2p14) in recent GWAS and liver fibrosis ( PNPLA3 ) in recent meta-analysis were analyzed for association with either liver cirrhosis or advanced fibrosis in 148 German HFE C282Y homozygotes. Replication of associations was sought in additional 499 Austrian/Swiss and 112 HFE C282Y homozygotes from Sweden. Only variant rs236918 in the PCSK7 gene (proprotein convertase subtilisin/kexin type 7) was associated with cirrhosis or advanced fibrosis ( P = 1.02 x 10 –5 ) in the German cohort with genotypic odds ratios of 3.56 (95% CI 1.29–9.77) for CG heterozygotes and 5.38 (95% CI 2.39–12.10) for C allele carriers. Association between rs236918 and cirrhosis was confirmed in Austrian/Swiss HFE C282Y homozygotes ( P = 0.014; OR allelic = 1.82 (95% CI 1.12–2.95) but not in Swedish patients. Post hoc combined analyses of German/Swiss/Austrian patients with available liver histology ( N = 244, P = 0.00014, OR allelic = 2.84) and of males only ( N = 431, P = 2.17 x 10 –5 , OR allelic = 2.54) were consistent with the premier finding. Association between rs236918 and cirrhosis was not confirmed in alcoholic cirrhotics, suggesting specificity of this genetic risk factor for HH. PCSK7 variant rs236918 is a risk factor for cirrhosis in HH patients homozygous for the HFE C282Y mutation.

Description: The assembly of 30S ribosomes requires the precise addition of 20 proteins to the 16S ribosomal RNA. How early binding proteins change the ribosomal RNA structure so that later proteins may join the complex is poorly understood. Here we use single-molecule fluorescence resonance energy transfer (FRET) to observe real-time encounters between Escherichia coli ribosomal protein S4 and the 16S 5' domain RNA at an early stage of 30S assembly. Dynamic initial S4-RNA complexes pass through a stable non-native intermediate before converting to the native complex, showing that non-native structures can offer a low free-energy path to protein-RNA recognition. Three-colour FRET and molecular dynamics simulations reveal how S4 changes the frequency and direction of RNA helix motions, guiding a conformational switch that enforces the hierarchy of protein addition. These protein-guided dynamics offer an alternative explanation for induced fit in RNA-protein complexes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3968076/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3968076/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, Hajin -- Abeysirigunawarden, Sanjaya C -- Chen, Ke -- Mayerle, Megan -- Ragunathan, Kaushik -- Luthey-Schulten, Zaida -- Ha, Taekjip -- Woodson, Sarah A -- R01 GM060819/GM/NIGMS NIH HHS/ -- R01 GM065367/GM/NIGMS NIH HHS/ -- R01 GM60819/GM/NIGMS NIH HHS/ -- R01 GM65367/GM/NIGMS NIH HHS/ -- T32 GM007231/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Feb 20;506(7488):334-8. doi: 10.1038/nature13039. Epub 2014 Feb 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Physics, Center for the Physics of Living Cells and Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA [2] Howard Hughes Medical Institute, Urbana, Illinois 61801, USA [3] [4] School of Nano-Bioscience and Chemical Engineering, Ulsan National Institute of Science and Technology, Ulsan 689-798, Republic of Korea (H.K.); Department of Biochemistry and Biophysics, University of California at San Francisco, 600 16th Street, San Francisco, California 94143-2200, USA (M.M.); Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, LHRRB-517, Boston, Massachusetts 02115-5730, USA (K.R.). ; 1] T. C. Jenkins Department of Biophysics, Johns Hopkins University, 3400 N. Charles Street, Baltimore, Maryland 21218, USA [2]. ; 1] Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA [2] Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA. ; 1] CMDB Program, Johns Hopkins University, 3400 N. Charles Street, Baltimore, Maryland 21218, USA [2] School of Nano-Bioscience and Chemical Engineering, Ulsan National Institute of Science and Technology, Ulsan 689-798, Republic of Korea (H.K.); Department of Biochemistry and Biophysics, University of California at San Francisco, 600 16th Street, San Francisco, California 94143-2200, USA (M.M.); Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, LHRRB-517, Boston, Massachusetts 02115-5730, USA (K.R.). ; 1] Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA [2] School of Nano-Bioscience and Chemical Engineering, Ulsan National Institute of Science and Technology, Ulsan 689-798, Republic of Korea (H.K.); Department of Biochemistry and Biophysics, University of California at San Francisco, 600 16th Street, San Francisco, California 94143-2200, USA (M.M.); Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, LHRRB-517, Boston, Massachusetts 02115-5730, USA (K.R.). ; 1] Department of Physics, Center for the Physics of Living Cells and Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA [2] Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA [3] Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA. ; 1] Department of Physics, Center for the Physics of Living Cells and Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA [2] Howard Hughes Medical Institute, Urbana, Illinois 61801, USA [3] Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA [4] Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA. ; 1] T. C. Jenkins Department of Biophysics, Johns Hopkins University, 3400 N. Charles Street, Baltimore, Maryland 21218, USA [2] CMDB Program, Johns Hopkins University, 3400 N. Charles Street, Baltimore, Maryland 21218, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24522531" target="_blank"〉PubMed〈/a〉