Formation of novel secondary metabolites by bacterial multimodular assembly lines: deviations from textbook biosynthetic logic

Microorganisms produce an immense variety of natural products with useful biological activities. These compounds are often biosynthesized by multifunctional megasynthetases known as polyketide synthases and nonribosomal peptide synthetases. Recent literature on these natural product assembly lines suggests that they have a much greater mechanistic diversity than originally anticipated.     

Predictors of belief that genetic test information about hemochromatosis should be shared with family members

We queried 101,951 white, Hispanic, black, Asian, American Indian (i.e., American Indian or Alaska Native in the United States and North American Indian, Metis, or Inuit in Canada) and Pacific Islander (including Native Hawaiian) adults who agreed to be genotypically and phenotypically screened for hemochromatosis as part of the Hemochromatosis and Iron Overload Screening (HEIRS) study about their views on sharing genetic test information with family members. Multiple logistic regression (adjusting for study site, age group, race/ethnicity, preferred language, gender, education group, income group, SF-36 General Health and Mental Health subscales, perceived benefits and limitations of genetic testing, and belief that genetic testing is a good idea) evaluated independent predictors of responding "Strongly Agree" or "Agree" versus "Disagree" or "Strongly Disagree" to the statement "Information about a person's genetic risk should be shared with family members". Agreement that genetic risk information should be shared with family members was high (93% in the overall sample of 78,952 who answered this question), but differed among racial/ethnic groups. Hispanics were significantly less likely to agree that genetic test information should be shared with family members (i.e., 88% versus 92% or more among all other ethnicities). The relationship of perceived limitations and benefits of testing, gender, and age group to the belief that information should be shared differed among racial/ethnic groups, with Spanish-preferring Hispanics being the most different from other subgroups.     

Interactions of the Human LIP5 Regulatory Protein with Endosomal Sorting Complexes Required for Transport

The endosomal sorting complex required for transport (ESCRT) pathway remodels membranes during multivesicular body biogenesis, the abscission stage of cytokinesis, and enveloped virus budding. The ESCRT-III and VPS4 ATPase complexes catalyze the membrane fission events associated with these processes, and the LIP5 protein helps regulate their interactions by binding directly to a subset of ESCRT-III proteins and to VPS4. We have investigated the biochemical and structural basis for different LIP5-ligand interactions and show that the first microtubule-interacting and trafficking (MIT) module of the tandem LIP5 MIT domain binds CHMP1B (and other ESCRT-III proteins) through canonical type 1 MIT-interacting motif (MIM1) interactions. In contrast, the second LIP5 MIT module binds with unusually high affinity to a novel MIM element within the ESCRT-III protein CHMP5. A solution structure of the relevant LIP5-CHMP5 complex reveals that CHMP5 helices 5 and 6 and adjacent linkers form an amphipathic “leucine collar” that wraps almost completely around the second LIP5 MIT module but makes only limited contacts with the first MIT module. LIP5 binds MIM1-containing ESCRT-III proteins and CHMP5 and VPS4 ligands independently in vitro, but these interactions are coupled within cells because formation of stable VPS4 complexes with both LIP5 and CHMP5 requires LIP5 to bind both a MIM1-containing ESCRT-III protein and CHMP5. Our studies thus reveal how the tandem MIT domain of LIP5 binds different types of ESCRT-III proteins, promoting assembly of active VPS4 enzymes on the polymeric ESCRT-III substrate.     

Das Vogelleben in Flur und Wald des deutsch-b?hmischen Mittelgebirges

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