There have been so many interesting research news over the last six months that I decide to give them all in one installment. It may make a good holiday reading. The first in this series is about proteins in general.
1. Exploring the limits of protein sequence space
Exploring the variability of individual functional proteins is complicated by the vast number of combinations of possible amino acid sequences. Podgornaia and Laub take on this challenge by analyzing four amino acids critical for the interaction between two signaling proteins in Escherichia coli. They build all the possible 160,000 variants of one of the two proteins and find that over 1650 are functional. Even though there can be very high variability in the composition of the interface between the two proteins, there are nonetheless strong context-dependent constraints for some amino acids, which suggests why many functional variants are not seen in nature. Science STKE 10 Feburary 2015.
Affordable antivirals used as vaginal microbicides could have a substantial impact on the HIV epidemic, particularly in the developing world. One potential candidate is cyanovirin-N, a protein produced by a cyanobacterium that prevents viral entry in preclinical studies. Large-scale production of cyanovirin-N, however, is prohibitively expensive. To get around this, O’Keefe et al. genetically engineered soybean seeds to make cyanovirin-N. The seeds produced large quantities of the antiviral and it survived the normal industrial processing systems already in place for soybeans. By rough estimate, one greenhouse growing engineered soybeans could provide enough cyanovirin-N to protect a woman for 90 years.
Plant Biotech. J. 10.1111/pbi.12309 (2015). Open access.
3. What are the genomic requirements for life?
To promote identification and understanding of the minimal set of genomic elements required for life, Lluch-Senar et al. studied M. pneumonia. This small bacterium has an 816-kb genome with about 700 open reading frames; about a third of the genome appeared to be essential. Small open reading frames, of less than 100 residues, made up slightly more than half of the essential components, and they appeared to encode components of larger protein, DNA, or RNA complexes. Protein domains, rather than complete proteins, were often the essential elements of larger proteins, whereas regulatory elements—5′ untranslated regions and noncoding RNAs—were also fundamental components.
Mol. Syst. Biol. 10.15252/msb.20145558 (2015).Open access.
4. RNA EDITING
During RNA editing, specific enzymes alter nucleotides in mRNA transcripts so that the resulting protein differs in amino acid sequence from what was encoded by the original DNA. Such RNA editing is a means to generate greater protein diversity; however, most organisms only use it sparingly. Alon et al., however, now report an exception. They sequenced RNA and DNA from the squid nervous system and discovered that 60% of the transcripts exhibited RNA editing. Such “recoding” occurred largely in genes with cytoskeletal or neuronal functions and may be advantageous to organisms such as squid that must respond quickly and continually to environmental changes.
eLife 4, e05198 (2015). Open access.
White blood cells called neutrophils recognize bacterial DNA, triggering a response that eventually kills the invaders. Zusen Fan and his colleagues at the Chinese Academy of Sciences Institute of Biophysics in Beijing found that a DNA-binding protein called Sox2 is also part of this bacterial surveillance system in mice and humans.
They discovered that Sox2 binds to bacterial DNA, and that bacterial infections were worse in mice that had been engineered to have no Sox2 expression in neutrophils. Infections were also worse in mice lacking another protein called TAB2, which interacts with Sox2. The findings could suggest new ways of treating infections, say the authors.
Nature 519, 8 (05 March 2015)
Marie-Thérèse Giudici-Orticoni of Aix-Marseille University, France, and her colleagues cultured Clostridium acetobutylicum, which uses glucose to grow, and Desulfovibrio vulgaris, which uses lactate and sulfate, in a medium containing only glucose. Desulfovibrio vulgaris attached itself to C. acetobutylicum, allowing it to share the other bacterium’s cytoplasm and proteins. This altered the metabolism of D. vulgaris, allowing it to grow with only glucose. Nature Communications 6, Article number:6283
In a separate study, Christian Kost of the Max Planck Institute for Chemical Ecology in Jena, Germany, and his colleagues mutated Escherichia coli and Acinetobacter baylyi so that they could not produce certain essential amino acids. When grown in a medium lacking the amino acid it required, E. coli formed nanotubes up to 14 micrometres long to connect with and share the cytoplasm of nearby A. baylyi, which was producing the amino acid. In return, E. coli provided A. baylyi with the amino acid it needed. These bacteria function as interconnected entities rather than individuals, the authors suggest. Nature Communications 6, Article number:6288
Although bacteria can help the immune system wage war against cancer, they can play for the other side, too. Gur et al. reveal one such example for the bacterium Fusobacterium nucleatum, which is found in human tumors such as colon adenocarcinomas. A protein on the bacteria (Fap2) binds to an inhibitory receptor called TIGIT expressed on the surface of natural killer cells and T cells, reducing their ability to kill bacteria-associated tumor cells in culture. Whether F. nucleatum plays a similar role in people with colon adenocarcinomas remains to be determined. Immunity 42, 344 (2015).
8. Disarming a cellular defense system
Macrophages are cells that engulf and destroy foreign substances in a process called phagocytosis. Lee et al. now show how a bacterium from the Yersinia family, which includes the bacteria that causes bubonic plague, acts to disable phagocytosis. Yersinia enterocolitica injects a protein called YopO into macrophages. A crystal structure shows that YopO binds to single host actin proteins in a way that prevents them from adding to actin filaments that form the skeleton of the cell. Moreover, the complex sequesters and phosphorylates proteins required for remodeling the actin skeleton, probably preventing the remodeling required for phagocytosis. Nat. Struct. Mol. Biol. 10.1038/nsmb.2964 (2015).
For T cells, fighting infections is demanding work. They must proliferate many times over and quickly produce a myriad of antimicrobial factors. T cells do this by switching from mitochondrial to glycolytic metabolism, but what happens when nutrients are scarce, such as in infected tissues or tumors? Blagih et al. examined this question by starving mouse T cells of glucose. They found that T cells are highly adaptable—they pulled back on protein translation, used glutamine as an energy source, and relied more on mitochondrial metabolism. The enzyme AMPK, an evolutionarily conserved energy sensor, facilitated these changes. Immunity 42, 41 (2015).