GABA (gamma-amino butyric acid) receptors belong to the group of pentameric ligand-gated ion channels as serotonin receptors or acetylcholin receptors. Since these membrane proteins have been impossible to chrystallize for a long time and there are still difficulties to determine their structure by X-ray spectometry. However, in recent years it became fashionable to analyze membrane receptors of different types, the determination of the GABA receptor is not a great surprise.
In this week Nature (doi:10.1038/nature13293) Miller and Aricescu from Oxford, UK, show the structure of the so-called β3-homopentamer. BTW that only two authors succeded in this task comes as a surprise.
The GABA receptor is involved in a number of diseases: epilepsy, insomnia, anxiety and panic disorders, has a role in alcohol abuse, binds to benzodiapines. Miller and Aricescu have chrystallized the receptor with a so far unkown agonist (a molecule to activate): benzamidine which allows predictions about the way ligands are bound and how they function.
The paper shows a abundance of beautiful structural graphs which were drawn with Pymol a nice program used by myself in Hormone und Hormonsystem.
PCB (PoylChlorinated Bisphenyls) are among the longlasting environmental toxins. They are present in varying degrees all over. It has been very difficult to identify bacteria which can degradate this chemical highly inert products enzymatically.
This weeks PNAS (doi: 10.1073/pnas.1404845111 ) describes for the first time the cultivation of organisms which can be reliably kept in culture and which feed on PCB. The authors show three Dehalococcoides mccartyi strains with different dechlorination potential and slight differences in the genome. The enzyme involved is a Reductive Dehalogenase which sequences have been determined and which are active in a bioassay removing chlorine from both PCB and PCE.
This may be a novel step in the search for decontamination, however, given that the process so far in under anaerobis conditions, it is mere speculation that this enzyme will work under ambient conditions.
The analysis of tumour remains fascinating. While e.g. viruses, methylation of DNA, gene silencing, mutations and deletions have been recognized for some time to play major roles in tumour development, a new player has emerged only recently: microRNA or miRNA. An Open Access review in Current Biology ( http://dx.doi.org/10.1016/j.cub.2014.06.043) features this new class of molecules and describes how they act on tumours. A must read!
Almost any animal regulates its metabolism as well as its reproductive life according to the time of the year. (The fact that some domestic animals do not is the exception). This dependence on the season has long been a mystery for endocrinologists. Even then it was found that the Nucleus suprachiasmaticus in the hypothalamus controls and generates a circadian (daily) rhythm which is reflected in all animals analyzed the circannual (yearly) rhythm remained obcur.
Recent developments have shown that some pituitary cells in Pars tuberalis (PT; close to the pituitary stalk) measure the length of day via the melatonin they receive. Since melatonin is only produced in the dark, much melatonin means long nights and few melatonin means short nights. These cells therefore have been named calendar cells.
In an Open Access review in the Journal of Endocrinology Shona Wood and Andrew Loudon have summarized what is known about the physiology and biochemistry of this circannual regulation. They show that thyriod hormones and their conversion from thyroxine to triiodothyronine by deiodinase are an important part in the short day response. They analyse the melatonin response in the PT. They also show how clock genes are differential regulated during the seasons. Finally they show that a ancient gene, the eye absent protein 3 (EYA3) is specifically upregulated when the days get longer.
These genes are ancient and found in insects as well as in birds and mammals pointing to a very old mechanism.
Nice paper, worth studying!
A LPS receptor has already been identified by Beutler and colleagues. This finding was awarded the NOBEL prize in 2011. In the actual issue of Nature (doi:10.1038/nature13683) Shi and colleagues describe the role of caspases – enzymes triggerung cell death called apoptosis – as intracellular receptors for LPS.
When LPS is delived intracellarly into macrophages, epithelial cells or keratinocytes these cells undergo necrosis. The process is specific for intact Lipid A. Murine caspase-11 as well as human caspases 4 and 5 bind to LPS and Lipid A. They induce what is called pyroptosis. The paper is nicely done, however, one might wonder when and how LPS is released from the phagolysosome and becomes available within a cell.
It has been already published in May this year, but I think it is still worth mentioning here:
Bloomberg (klick on the link to see the orginal article) reports that dogs can be trained to sniff whether a person has breast cancer or prostate cancer. The selectivity, by which dogs discriminate between positive and negative samples is 90% and more. If we could train our dogs to do so, all mamma screening e.g. would become obsolete. We do not know what substances the dogs smell, but we can envisage that once they are identified we could train enough dogs to do the job or analytical chemistry might be able to do so. One would hope that dogs will be used because the test would be ultimately cheaper and emotionally closer than in the case of chemistry.
A nice analysis of the trimethylation of histon 3 at lysine 4 (H3K4me3) appears in Cell this week (http://dx.doi.org/10.1016/j.cell.2014.06.027). Benayoun and Pollina et al. claim that this marker labels preferentially those proteins that are essential for the cell’s function. The marker has been found at the start of most transcribed genes, but Benayoun and Pollina argue that not its mere presence, but the intensity of its presence is a sign that this protein is relevant for lineage specifity. If this intensity is disturbed, that function is not maintained.
This is a metaanalysis of a very broad range including human, mammalian, protostomes, plants and fungi. Nicely done!
Gerald Maurice Edelman died in La Jolla California at the age of 84.
Immunologist worldwide recognize him for his contribution to the antibody enigma. Trained in medicine and chemistry his first publication on antibodies established that these molecules can be subjected to urea and sulfhydryl treatment and yield smaller chains as we know now very well but was new in 1959 when first published. For his work on antibody strucuture which e.g. lead to the first sequence of Ig γ-chain he was awarded the Nobel Prize in 1972 together with Rodney R. Porter.
The antibody enigma was only solved by Susumu Tonegawa who showed that recombination of the same DNA could lead to millions of different mRNAs from which finally antibody molecules are translated. He obtained the Nobel Prize in 1987 as well.
Faithfull translation of mRNA into proteins is one of the hallmarks of life. It is generally accepted that any deviation from this pathway leads to missformed proteins and is considered deleterious per se.
A very enlightning review in Trends in Biological Sciences (TIBS; DOI: 10.1016/j.tibs.2014.06.002) shows that errors in translation are dealt with in a productive way. First of all mistranslation are obviously regulated due to species and environnement which is by itself showing that mistranslation is beneficial for the organism, at least part of it. Furthermore mistranslation is well tolerated and not deleterious for the organism. Different organisms have evolved strategies to deal with it. It seems clear that by mistranslation the organism generates alternative proteins which may help to adapt the different environmental challenges.