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Wayne Hendrickson discusses the consortium efforts and developments in methodology that in recent years have allowed unprecedented advances in atomic-structure determination of membrane proteins.
Telomerase is a nucleoprotein complex of a reverse transcriptase and an RNA that binds complementary telomeric-repeat DNA sequences and directs their extension. In this Commentary, the authors propose how hairpin structures formed by telomeric DNA repeats promote addition of telomerase repeats and why telomere sequences are evolutionarily conserved despite the problems that they pose to DNA replication.
Cellular fate is determined by transcriptional networks and epigenetic states. In addition to protein factors, noncoding RNAs (ncRNAs), particularly microRNAs and long ncRNAs, are able to remodel transcriptional circuits and reshape epigenetic landscapes. This Commentary highlights the emerging roles of these ncRNAs in cellular reprogramming, transdifferentiation and organ regeneration.
Recent advances in RNA-sequencing technologies have led to the discovery of thousands of previously unannotated noncoding transcripts, including many long noncoding RNAs (lncRNAs) whose functions remain largely unknown. Here, the authors discuss considerations and best practices when identifying and annotating lncRNAs that should aid their functional and mechanistic exploration.
The natural versatility of RNA makes it an ideal substrate for bioengineering. Its structural properties and predictable base-pairing permit its use as molecular scaffold, and its ability to interact with nucleic acids, proteins and small molecules confers a regulatory potential that can be harvested to design RNA regulators in diverse contexts.
We report the outcomes of the discussion initiated at the workshop entitled A 3D Cellular Context for the Macromolecular World and propose how data from emerging three-dimensional (3D) cellular imaging techniques—such as electron tomography, 3D scanning electron microscopy and soft X-ray tomography—should be archived, curated, validated and disseminated, to enable their interpretation and reuse by the biomedical community.
The past decade has witnessed an explosion in the identification of ubiquitin-ligase complexes as the missing receptors for important small-molecule hormones regulating plant growth and development. These breakthroughs were initiated by genetic approaches, with structural analysis providing mechanistic insights into how hormone perception and signaling are coupled to protein ubiquitination. Although there are still many unknowns, plants have imparted valuable lessons about the pharmacology of ubiquitin modification.
Protein homeostasis is essential for cellular function, organismal growth and viability. Damaged and aggregated proteins are turned over by two major proteolytic routes of the cellular quality-control pathways: the ubiquitin-proteasome system and autophagy. For both these pathways, ubiquitination provides the recognition signal for substrate selection. This Commentary discusses how ubiquitin-dependent proteolytic pathways are coordinated with stress- and aging-induced signals.
The immune system must operate in an effective, precise and safe manner to defend against diverse pathogens while avoiding attacking the body itself and commensal bacteria. Inflammatory pathways mediated by NOD-like, Toll-like, RIG-I–like and tumor-necrosis-factor receptor families are tightly regulated by ubiquitination, especially by Lys63-linked and linear polyubiquitin chains. Here we discuss the human ubiquitin-mediated inflammatory signaling system, emphasizing the interactions and activities whose coordination ensures timely, accurate regulation of inflammatory responses.
Given the recent successes in determining membrane-protein structures, we explore the tractability of determining representatives for the entire human membrane proteome. This proteome contains 2,925 unique integral α-helical transmembrane-domain sequences that cluster into 1,201 families sharing more than 25% sequence identity. Structures of 100 optimally selected targets would increase the fraction of modelable human α-helical transmembrane domains from 26% to 58%, providing structure and function information not otherwise available.
This report describes the outcomes of the Data Management Challenges in 3D Electron Microscopy workshop. Key topics discussed include data models, validation and raw-data archiving. The meeting participants agreed that the EMDataBank should take the lead in addressing these issues, and concrete action points were agreed upon that will have a substantial impact on the accessibility of three-dimensional EM data in biology and medicine.
Until recently, few potent and broadly neutralizing HIV-specific antibodies had been identified, but recent findings have inspired optimism that an effective HIV vaccine can finally be developed. Here we review these studies, which used state-of-the-art high-throughput techniques to collectively describe hundreds of new potent and broad HIV-neutralizing antibodies isolated from HIV-infected individuals.
How does a transcription factor select a specific DNA response element given the presence of degenerate sequences? To date, this question has largely been viewed from the standpoint of DNA sequence variability and transcription factor binding affinity under steady-state conditions. Here we propose that to address this problem, it is also necessary to account for fluctuating cellular conditions. These lead to dynamic changes in the ensemble of protein (and DNA) conformational states via allosteric effects.
The WD40 protein WDR5 is a core subunit of the human MLL and SET1 (hCOMPASS) histone H3 Lys4 (H3K4) methyltransferase complexes. Although initial studies suggested that WDR5 interacts with methylated H3K4 to catalyze Lys4 trimethylation, recent work has revealed that it binds an arginine-bearing motif in MLL1, promoting complex assembly and activity. These findings suggest that WDR5 functions as a peptidyl arginine–recognition factor that facilitates the assembly of hCOMPASS and other chromatin-modifying complexes.
Eukaryotes transcribe much of their genomes, but little is known about the fidelity of transcriptional initiation by RNA polymerase II in vivo. I suggest that ∼90% of Pol II initiation events in yeast represent transcriptional noise, and that the specificity of initiation is comparable to that of DNA-binding proteins and other biological processes. This emphasizes the need to develop criteria that distinguish transcriptional noise from transcription with a biological function.
The tails of the four core histones are exposed on the nucleosome surface, where they are subject to a variety of enzyme-catalyzed, post-translational modifications. Modifications, singly or in combination, provide a source of information that can be used for signal transduction during ongoing processes, such as transcription, or as heritable epigenetic marks. A nomenclature is presented that allows patterns of histone modification to be clearly and unambiguously specified and that should facilitate discussion of their functional roles.
The research in biology has been transformed by the products of interdisciplinary research. Here we explore why it is challenging for universities to bring biologists together with engineers, physicists and computer scientists for productive collaboration, and we evaluate alternative solutions. In particular, we describe how the new Janelia Farm Research Campus of Howard Hughes Medical Institute aims to provide a home for creative scientists from different disciplines to attack major biomedical research problems.
