tRNA nucleotidyltransferase adds the invariant CCA‐terminus to the tRNA 3′‐end, a central step in tRNA maturation. This CCA‐adding enzyme is a specialized RNA polymerase that synthesizes the CCA sequence at high fidelity in all kingdoms of life. Recently, an additional function of this enzyme was identified, where it generates a specific degradation tag on structurally unstable tRNAs. This tag consists of an additional repeat of the CCA triplet, leading to a 3′‐terminal CCACCA sequence. In order to explain how the enzyme (...) catalyzes this extended polymerization reaction, Kuhn et al. solved a series of co‐crystal structures of the CCA‐adding enzyme from Archaeoglobus fulgidus in complex with different tRNA substrates. They show that the enzyme forces a bound unstable tRNA to refold the acceptor stem for a second round of CCA‐addition, while stable transcripts are robust enough to resist this isomerization. In this review, we discuss how the CCA‐adding enzyme uses a simple yet very elegant way to scrutinize its substrates for sufficient structural stability and, consequently, functionality. (shrink)

Molecular chaperones in cells constantly monitor and bind to exposed hydrophobicity in newly synthesized proteins and assist them in folding or targeting to cellular membranes for insertion. However, proteins can be misfolded or mistargeted, which often causes hydrophobic amino acids to be exposed to the aqueous cytosol. Again, chaperones recognize exposed hydrophobicity in these proteins to prevent nonspecific interactions and aggregation, which are harmful to cells. The chaperone‐bound misfolded proteins are then decorated with ubiquitin chains denoting them for proteasomal degradation. (...) It remains enigmatic how molecular chaperones can mediate both maturation of nascent proteins and ubiquitination of misfolded proteins solely based on their exposed hydrophobic signals. In this review, we propose a dynamic ubiquitination and deubiquitination model in which ubiquitination of newly synthesized proteins serves as a “fix me” signal for either refolding of soluble proteins or retargeting of membrane proteins with the help of chaperones and deubiquitinases. Such a model would provide additional time for aberrant nascent proteins to fold or route for membrane insertion, thus avoiding excessive protein degradation and saving cellular energy spent on protein synthesis. Also see the video abstract here: https://youtu.be/gkElfmqaKG4. (shrink)

The coupling of protein synthesis and folding is a crucial yet poorly understood aspect of cellular protein folding. Over the past few years, it has become possible to experimentally follow and define protein folding on the ribosome, revealing principles that shape co‐translational folding and distinguish it from refolding in solution. Here, we highlight some of these recent findings from biochemical and biophysical studies and their potential significance for cellular protein biogenesis. In particular, we focus on nascent chain interactions with (...) the ribosome, interactions within the nascent protein, modulation of translation elongation rates, and the role of mechanical force that accompanies nascent protein folding. The ability to obtain mechanistic insight in molecular detail has set the stage for exploring the intricate process of nascent protein folding. We believe that the aspects discussed here will be generally important for understanding how protein synthesis and folding are coupled and regulated. (shrink)

Molecular chaperones assist de novo protein folding and facilitate the refolding of stress‐denatured proteins. The molecular chaperone concept was coined nearly 35 years ago, and since then, tremendous strides have been made in understanding how these factors support protein folding. Here, we focus on how various chaperone proteins were first identified to play roles in protein folding. Examples are used to illustrate traditional routes of chaperone discovery and point out their advantages and limitations. Recent advances, including the development of (...) folding biosensors and promising methods for the stabilization of proteins in vivo, provide new routes for chaperone discovery. (shrink)

Many contemporary conceptualizations of terrorism inadvertently reify political conceptions of terrorism. Mainly because they in the end rely on the intentions of terrorists in defining ‘terrorism’, the process of terrorism, which involves an unfolding dialectic of actions and reactions, is omitted from researchers’ focus. Thus, terrorism becomes simplified to intentional actions by terrorists, and this short-cutting of the causal chain of the process of terrorism facilitates both a political ‘negation of history’ and a ‘rhetoric of response’. In this paper, I (...) put forward a conceptualization of terrorism that transcends existing definitions and conceptualizations by first of all discerning between ‘terrorism’ and ‘terror’, and by subsequently conceptualizing terrorism as a paradox: what terrorism is, is inextricably bound to the reaction to terrorism. It is, in fact, the reaction of some states to terrorism that, in a sense ex post facto, constitutes an act as ‘terrorism’ by ‘refolding’ actions that unfolded subsequent to an event into that event as the root cause of the entire chain of events. (shrink)

In a short paper bearing the title “The Deleuzian Fold of Thought” (1996), Jean-Luc Nancy engages a concept that has a prominent place in contemporary continental philosophy, the fold, so as to accentuate a shared tendency that nevertheless estranges his own thought from Gilles Deleuze’s. This shared tendency deals with the shifting conception of thinking through the fold itself, the unfolding and refolding of the fold, which in its discontinuity has transformed the image of what it means to think. (...) I do not seek to reconcile the two thinkers through the fold, but to demonstrate the way in which their estrangement through the fold is what it means to think and defines the exigency of thought. (shrink)

In a short paper bearing the title “The Deleuzian Fold of Thought”, Jean-Luc Nancy engages a concept that has a prominent place in contemporary continental philosophy, the fold, so as to accentuate a shared tendency that nevertheless estranges his own thought from Gilles Deleuze’s. This shared tendency deals with the shifting conception of thinking through the fold itself, the unfolding and refolding of the fold, which in its discontinuity has transformed the image of what it means to think. I (...) do not seek to reconcile the two thinkers through the fold, but to demonstrate the way in which their estrangement through the fold is what it means to think and defines the exigency of thought. (shrink)

Chromosomes are not randomly packed and positioned into the nucleus but folded in higher‐order chromatin structures with defined functions. However, the genome of a fertilized embryo undergoes a dramatic epigenetic reprogramming characterized by extensive chromatin relaxation and the lack of a defined three‐dimensional structure. This reprogramming is followed by a slow genome refolding that gradually strengthens the chromatin architecture during preimplantation development. Interestingly, genome refolding during early development coincides with a progressive loss of developmental potential suggesting a link (...) between chromatin organization and cell plasticity. In agreement, loss of chromatin architecture upon depletion of the insulator transcription factor CTCF in embryonic stem cells led to the upregulation of the transcriptional program found in totipotent cells of the embryo, those with the highest developmental potential. This essay will discuss the impact of genome folding in controlling the expression of transcriptional programs involved in early development and their plastic‐associated features. (shrink)

Numerous accessory factors modulate RNA polymerase response to regulatory signals and cellular cues and establish communications with co‐transcriptional RNA processing. Transcription regulators are astonishingly diverse, with similar mechanisms arising via convergent evolution. NusG/Spt5 elongation factors comprise the only universally conserved and ancient family of regulators. They bind to the conserved clamp helices domain of RNA polymerase, which also interacts with non‐homologous initiation factors in all domains of life, and reach across the DNA channel to form processivity clamps that enable uninterrupted (...) RNA chain synthesis. In addition to this ubiquitous function, NusG homologs exert diverse, and sometimes opposite, effects on gene expression by competing with each other and other regulators for binding to the clamp helices and by recruiting auxiliary factors that facilitate termination, antitermination, splicing, translation, etc. This surprisingly diverse range of activities and the underlying unprecedented structural changes make studies of these “transformer” proteins both challenging and rewarding. (shrink)