Determining Protein Complex Connectivity Using a Probabilistic Deletion Network Derived from Quantitative Proteomics

Protein complexes are key molecular machines executing a variety of essential cellular processes. Despite the availability of genome-wide protein-protein interaction studies, determining the connectivity between proteins within a complex remains a major challenge. Here we demonstrate a method that is able to predict the relationship of proteins within a stable protein complex. We employed a combination of computational approaches and a systematic collection of quantitative proteomics data from wild-type and deletion strain purifications to build a quantitative deletion-interaction network map and subsequently convert the resulting data into an interdependency-interaction model of a complex. We applied this approach to a data set generated from components of the Saccharomyces cerevisiae Rpd3 histone deacetylase complexes, which consists of two distinct small and large complexes that are held together by a module consisting of Rpd3, Sin3 and Ume1. The resulting representation reveals new protein-protein interactions and new submodule relationships, providing novel information for mapping the functional organization of a complex.     

Mechanisms of neuroprotection by hemopexin: modeling the control of heme and iron homeostasis in brain neurons in inflammatory states

Hemopexin provides neuroprotection in mouse models of stroke and intracerebral hemorrhage and protects neurons in vitro against heme or reactive oxygen species (ROS) toxicity via heme oxygenase‐1 (HO1) activity. To model human brain neurons experiencing hemorrhages and inflammation, we used human neuroblastoma cells, heme–hemopexin complexes, and physiologically relevant ROS, for example, H₂O₂ and HOCl, to provide novel insights into the underlying mechanism whereby hemopexin safely maintains heme and iron homeostasis. Human amyloid precursor protein (hAPP), needed for iron export from neurons, is induced ~twofold after heme–hemopexin endocytosis by iron from heme catabolism via the iron‐regulatory element of hAPP mRNA. Heme–hemopexin is relatively resistant to damage by ROS and retains its ability to induce the cytoprotective HO1 after exposure to tert‐butylhydroperoxide, although induction is impaired, but not eliminated, by exposure to high concentrations of H₂O₂ in vitro. Apo‐hemopexin, which predominates in non‐hemolytic states, resists damage by H₂O₂ and HOCl, except for the highest concentrations likely in vivo. Heme–albumin and albumin are preferential targets for ROS; thus, albumin protects hemopexin in biological fluids like CSF and plasma where it is abundant. These observations provide strong evidence that hemopexin will be neuroprotective after traumatic brain injury, with heme release in the CNS, and during the ensuing inflammation. Hemopexin sequesters heme, thus preventing unregulated heme uptake that leads to toxicity; it safely delivers heme to neuronal cells; and it activates the induction of proteins including HO1 and hAPP that keep heme and iron at safe levels in neurons.     

Regulation of the CRL4Cdt2 Ubiquitin Ligase and Cell-Cycle Exit by the SCFFbxo11 Ubiquitin Ligase

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Highlights? FBXO11 targets CDT2, a CRL4 substrate receptor, for proteasomal degradation ? CDK-mediated phosphorylation of CDT2 degron inhibits recognition by FBXO11 ? FBXO11-mediated degradation of CDT2 controls the timing of cell-cycle exit ? FBXO11-CDT2 functional interaction is evolutionary conserved from worms to humans     

Identifying cis Elements for Spatiotemporal Control of Mammalian DNA Replication

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Progressive heterosis in genetically defined tetraploid maize

Progressive heterosis, i.e., the additional hybrid vigor in double-cross tetraploid hybrids not found in their single-cross tetraploid parents, has been documented in a number of species including alfalfa,potato, and maize. In this study, four artificially induced maize tetraploids, directly derived from standard inbred lines, were crossed in pairs to create two single-cross hybrids. These hybrids were then crossed to create double-cross hybrids containing genetic material from all four original lines. Replicated fieldbased phenotyping of the materials over four years indicated a strong progressive heterosis phenotype in tetraploids but not in their diploid counterparts. In particular, the above ground dry weight phenotype of double-cross tetraploid hybrids was on average 34% and 56% heavier than that of the single-cross tetraploid hybrids and the double-cross diploid counterparts, respectively. Additionally,whole-genome resequencing of the original inbred lines and further analysis of these data did not show the expected spectrum of alleles to explain tetraploid progressive heterosis under the complementation of complete recessive model. These results underscore the reality of the progressive heterosis phenotype,its potential utility for increasing crop biomass production, and the need for exploring alternative hypothesis to explain it at a molecular level.     

Anthropological Advocacy in the Hopi-Navajo Land Dispute

The text of this commentary is derived from a talk given at the 86th annual meeting of the American Anthropological Association, Chicago, November 1987.