Bacterial swimming strategies and turbulence

Most bacteria in the ocean can be motile. Chemotaxis allows bacteria to detect nutrient gradients, and hence motility is believed to serve as a method of approaching sources of food. This picture is well established in a stagnant environment. In the ocean a shear microenvironment is associated with turbulence. This shear flow prevents clustering of bacteria around local nutrient sources if they swim in the commonly assumed "run-and-tumble" strategy. Recent observations, however, indicate a "back-and-forth" swimming behavior for marine bacteria. In a theoretical study we compare the two bacterial swimming strategies in a realistic ocean environment. The "back-and-forth" strategy is found to enable the bacteria to stay close to a nutrient source even under high shear. Furthermore, rotational diffusion driven by thermal noise can significantly enhance the efficiency of this strategy. The superiority of the "back-and-forth" strategy suggests that bacterial motility has a control function rather than an approach function under turbulent conditions.     

Transcriptional response to alcohol exposure in Drosophila melanogaster

Background  

Alcoholism presents widespread social and human health problems. Alcohol sensitivity, the development of tolerance to alcohol and susceptibility to addiction vary in the population. Genetic factors that predispose to alcoholism remain largely unknown due to extensive genetic and environmental variation in human populations. Drosophila, however, allows studies on genetically identical individuals in controlled environments. Although addiction to alcohol has not been demonstrated in Drosophila, flies show responses to alcohol exposure that resemble human intoxication, including hyperactivity, loss of postural control, sedation, and exposure-dependent development of tolerance.     

The genetic basis of alcoholism: multiple phenotypes,many genes,complex networks

Alcoholism is a significant public health problem. A picture of the genetic architecture underlying alcohol-related phenotypes is emerging from genome-wide association studies and work on genetically tractable model organisms.     

Predicting the points of interaction of small molecules in the NF-κB pathway

Background  

The similarity property principle has been used extensively in drug discovery to identify small compounds that interact with specific drug targets. Here we show it can be applied to identify the interactions of small molecules within the NF-κB signalling pathway.     

Human Naa50p (Nat5/San) Displays Both Protein Nα- and N?-Acetyltransferase Activity

Protein acetylation is a widespread modification that is mediated by site-selective acetyltransferases. KATs (lysine N^ϵ-acetyltransferases), modify the side chain of specific lysines on histones and other proteins, a central process in regulating gene expression. N^α-terminal acetylation occurs on the ribosome where the α amino group of nascent polypeptides is acetylated by NATs (N-terminal acetyltransferase). In yeast, three different NAT complexes were identified NatA, NatB, and NatC. NatA is composed of two main subunits, the catalytic subunit Naa10p (Ard1p) and Naa15p (Nat1p). Naa50p (Nat5) is physically associated with NatA. In man, hNaa50p was shown to have acetyltransferase activity and to be important for chromosome segregation. In this study, we used purified recombinant hNaa50p and multiple oligopeptide substrates to identify and characterize an N^α-acetyltransferase activity of hNaa50p. As the preferred substrate this activity acetylates oligopeptides with N termini Met-Leu-Xxx-Pro. Furthermore, hNaa50p autoacetylates lysines 34, 37, and 140 in vitro, modulating hNaa50p substrate specificity. In addition, histone 4 was detected as a hNaa50p KAT substrate in vitro. Our findings thus provide the first experimental evidence of an enzyme having both KAT and NAT activities.     

The Chaperone-Like Protein HYPK Acts Together with NatA in Cotranslational N-Terminal Acetylation and Prevention of Huntingtin Aggregation

The human NatA protein N^α-terminal-acetyltransferase complex is responsible for cotranslational N-terminal acetylation of proteins with Ser, Ala, Thr, Gly, and Val N termini. The NatA complex is composed of the catalytic subunit hNaa10p (hArd1) and the auxiliary subunit hNaa15p (hNat1/NATH). Using immunoprecipitation coupled with mass spectrometry, we identified endogenous HYPK, a Huntingtin (Htt)-interacting protein, as a novel stable interactor of NatA. HYPK has chaperone-like properties preventing Htt aggregation. HYPK, hNaa10p, and hNaa15p were associated with polysome fractions, indicating a function of HYPK associated with the NatA complex during protein translation. Knockdown of both hNAA10 and hNAA15 decreased HYPK protein levels, possibly indicating that NatA is required for the stability of HYPK. The biological importance of HYPK was evident from HYPK-knockdown HeLa cells displaying apoptosis and cell cycle arrest in the G₀/G₁ phase. Knockdown of HYPK or hNAA10 resulted in increased aggregation of an Htt-enhanced green fluorescent protein (Htt-EGFP) fusion with expanded polyglutamine stretches, suggesting that both HYPK and NatA prevent Htt aggregation. Furthermore, we demonstrated that HYPK is required for N-terminal acetylation of the known in vivo NatA substrate protein PCNP. Taken together, the data indicate that the physical interaction between HYPK and NatA seems to be of functional importance both for Htt aggregation and for N-terminal acetylation.N^α-terminal acetylation is among the most common protein modifications in eukaryotes, occurring on ∼50% of Saccharomyces cerevisiae proteins and ∼80% of human proteins (12). In yeast, four types of N^α-terminal acetyltransferases (NATs) have been defined (NatA-NatD), while a fifth type, NatE, has been hypothesized (21, 32-34, 38). For humans, NatA, NatB, NatC, and NatE were recently presented (2, 4, 18, 39, 40). A revised NAT-subunit nomenclature was recently introduced in order to have identical names for orthologous subunits from different species, and each gene was denoted NAA (N^α-acetyltransferase) followed by a number depending on Nat type and the type of subunit (catalytic/auxiliary) (32). The major human NAT complex, hNatA, is composed of the catalytic subunit hNaa10p (previously named hArd1) and the auxiliary subunit hNaa15p (hNat1/NATH) (4). Human NatA is evolutionarily conserved from the yeast complex in terms of subunit composition and substrate specificity (12, 26, 28). However, in contrast to yeast cells, human cells potentially contain several distinct NatA complexes due to the presence of two genes for each of the two NatA subunits, NAA10 and NAA15 (6, 8). Protein N-terminal acetylation occurs on the ribosome when the nascent polypeptide emerges (21, 29, 30, 41, 42). Proteins with Ser, Thr, Gly, Ala, Val, or Cys N termini are potential substrates of NatA (12), while NatB and NatC potentially acetylate specific classes of substrates that still carry the initiator Met (34). The biological importance of the human NatA complex was evident from knockdown experiments where induction of apoptosis and growth arrest of cells in the G₁/G₀ phase were the resulting phenotypes (9, 11, 20, 25). The phenotypes induced by hNatA depletion most likely reflect the fact that one or more specific substrate proteins lack proper N^α acetylation, in view of the fact that a large quantitative proteomic analysis of the acetylation status of protein N termini in hNaa15p-hNaa10p knockdown cells revealed a decrease in the level of N^α acetylation of some partially acetylated substrates compared to that in control cells (12).To further characterize the human NatA complex, we looked for the presence of stable interaction partners of hNaa15p and hNaa10p. Here we present data identifying the Huntingtin (Htt) yeast two-hybrid protein K (HYPK) as a novel factor involved in cotranslational NatA acetylation. HYPK, originally identified in a yeast two-hybrid screen during a search for potential interaction partners for the Huntingtin protein (19), was recently found to reduce Htt polyglutamine (polyQ) aggregation upon overexpression (36). However, the role of the endogenous HYPK protein has yet to be revealed. We demonstrate that endogenous HYPK (i) stably interacts with the hNaa10p-hNaa15p NatA N-terminal-acetyltransferase complex and with ribosomes, (ii) is required for normal N-terminal acetylation of a NatA substrate, (iii) is important for cell survival independent of Htt polyQ, and (iv) is important for the prevention of Htt polyQ aggregation. Furthermore, NatA is essential for the proper expression of HYPK protein and modulates Htt polyQ aggregation.