Quarterly Reviews Of Biophysics[JOURNAL]
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200 papers
Folding of copper proteins: role of the metal?
Ariöz C, Wittung-Stafshede P
Q Rev Biophys · 2018 Jan · PMID 30912494 · Publisher ↗
Copper is a redox-active transition metal ion required for the function of many essential human proteins. For biosynthesis of proteins coordinating copper, the metal may bind before, during or after folding of the polype...
Copper is a redox-active transition metal ion required for the function of many essential human proteins. For biosynthesis of proteins coordinating copper, the metal may bind before, during or after folding of the polypeptide. If the metal binds to unfolded or partially folded structures of the protein, such coordination may modulate the folding reaction. The molecular understanding of how copper is incorporated into proteins requires descriptions of chemical, thermodynamic, kinetic and structural parameters involved in the formation of protein-metal complexes. Because free copper ions are toxic, living systems have elaborate copper-transport systems that include particular proteins that facilitate efficient and specific delivery of copper ions to target proteins. Therefore, these pathways become an integral part of copper protein folding in vivo. This review summarizes biophysical-molecular in vitro work assessing the role of copper in folding and stability of copper-binding proteins as well as protein-protein copper exchange reactions between human copper transport proteins. We also describe some recent findings about the participation of copper ions and copper proteins in protein misfolding and aggregation reactions in vitro.
Copper chaperone blocks amyloid formation via ternary complex.
Horvath I, Werner T, Kumar R … +1 more , Wittung-Stafshede P
Q Rev Biophys · 2018 Jan · PMID 30912493 · Publisher ↗
Protein misfolding in cells is avoided by a network of protein chaperones that detect misfolded or partially folded species. When proteins escape these control systems, misfolding may result in protein aggregation and am...
Protein misfolding in cells is avoided by a network of protein chaperones that detect misfolded or partially folded species. When proteins escape these control systems, misfolding may result in protein aggregation and amyloid formation. We here show that aggregation of the amyloidogenic protein α-synuclein (αS), the key player in Parkinson's disease, is controlled by the copper transport protein Atox1 in vitro. Copper ions are not freely available in the cellular environment, but when provided by Atox1, the resulting copper-dependent ternary complex blocks αS aggregation. Because the same inhibition was found for a truncated version of αS, lacking the C-terminal part, it appears that Atox1 interacts with the N-terminal copper site in αS. Metal-dependent chaperoning may be yet another manner in which cells control its proteome.
RecA kinetically selects homologous DNA by testing a five- or six-nucleotide matching sequence and deforming the second DNA.
Takahashi M
Q Rev Biophys · 2018 Jan · PMID 30912492 · Publisher ↗
RecA family proteins pair two DNAs with the same sequence to promote strand exchange during homologous recombination. To understand how RecA proteins search for and recognize homology, we sought to determine the length o...
RecA family proteins pair two DNAs with the same sequence to promote strand exchange during homologous recombination. To understand how RecA proteins search for and recognize homology, we sought to determine the length of homologous sequence that permits RecA to start its reaction. Specifically, we analyzed the effect of sequence heterogeneity on the association rate of homologous DNA with RecA/single-stranded DNA complex. We assumed that the reaction can start with equal likelihood at any point in the DNA, and that sequence heterogeneity abolishes some possible initiation sites. This analysis revealed that the effective recognition size is five or six nucleotides, larger than the three nucleotides recognized by a RecA monomer. Because the first DNA is elongated 1.5-fold by intercalation of amino acid residues of RecA every three bases, the second bound DNA must be elongated to pair with the first. Because this length is similar to estimates based on the strand-exchange reaction or DNA pair formation, the homology test is likely to occur primarily at the association step. The energetic difference due to the absence of hydrogen bonding is too small to discriminate single-nucleotide heterogeneity over a five- or six-nucleotide sequence. The selection is very likely to be made kinetically, and probably involves some structural factor other than Watson-Crick hydrogen bonding. It would be valuable to determine whether this is also the case for other biological reactions involving DNA base complementarity, such as replication, transcription, and translation.
Former QRB Editor Richard Henderson awarded the Nobel Prize.
Nordén B, Lilley D
Q Rev Biophys · 2018 Jan · PMID 30912491 · Publisher ↗
Abstract loading — click title to view on PubMed.
The kink-turn in the structural biology of RNA.
Huang L, Lilley DMJ
Q Rev Biophys · 2018 Jan · PMID 30912490 · Publisher ↗
The kink-turn (k-turn) is a widespread structural motif found in functional RNA species. It typically comprises a three-nucleotide bulge followed by tandem trans sugar edge-Hoogsteen G:A base pairs. It introduces a sharp...
The kink-turn (k-turn) is a widespread structural motif found in functional RNA species. It typically comprises a three-nucleotide bulge followed by tandem trans sugar edge-Hoogsteen G:A base pairs. It introduces a sharp kink into the axis of duplex RNA, juxtaposing the minor grooves. Cross-strand H-bonds form at the interface, accepted by the conserved adenine nucleobases of the G:A basepairs. Alternative acceptors for one of these divides the k-turns into two conformational classes N3 and N1. The base pair that follows the G:A pairs (3b:3n) determines which conformation is adopted by a given k-turn. k-turns often mediate tertiary contacts in folded RNA species and frequently bind proteins. Common k-turn binding proteins include members of the L7Ae family, such as the human 15·5k protein. A recognition helix within these proteins binds in the widened major groove on the outside of the k-turn, that makes specific H-bonds with the conserved guanine nucleobases of the G:A pairs. L7Ae binds with extremely high affinity, and single-molecule data are consistent with folding by conformational selection. The standard, simple k-turn can be elaborated in a variety of ways, that include the complex k-turns and the k-junctions. In free solution in the absence of added metal ions or protein k-turns do not adopt the tightly-kinked conformation. They undergo folding by the binding of proteins, by the formation of tertiary contacts, and some (but not all) will fold on the addition of metal ions. Whether or not folding occurs in the presence of metal ions depends on local sequence, including the 3b:3n position, and the -1b:-1n position (5' to the bulge). In most cases -1b:-1n = C:G, so that the 3b:3n position is critical since it determines both folding properties and conformation. In general, the selection of these sequence matches a given k-turn to its biological requirements. The k-turn structure is now very well understood, to the point at which they can be used as a building block for the formation of RNA nano-objects, including triangles and squares.
The enigmatic ribosomal stalk.
Liljas A, Sanyal S
Q Rev Biophys · 2018 Jan · PMID 30912488 · Publisher ↗
The large ribosomal subunit has a distinct feature, the stalk, extending outside the ribosome. In bacteria it is called the L12 stalk. The base of the stalk is protein uL10 to which two or three dimers of proteins bL12 b...
The large ribosomal subunit has a distinct feature, the stalk, extending outside the ribosome. In bacteria it is called the L12 stalk. The base of the stalk is protein uL10 to which two or three dimers of proteins bL12 bind. In archea and eukarya P1 and P2 proteins constitute the stalk. All these extending proteins, that have a high degree of flexibility due to a hinge between their N- and C-terminal parts, are essential for proper functionalization of some of the translation factors. The role of the stalk proteins has remained enigmatic for decades but is gradually approaching an understanding. In this review we summarise the knowhow about the structure and function of the ribosomal stalk till date starting from the early phase of ribosome research.
Thermodynamic, kinetic, and structural parameterization of human carbonic anhydrase interactions toward enhanced inhibitor design.
Linkuvienė V, Zubrienė A, Manakova E … +7 more , Petrauskas V, Baranauskienė L, Zakšauskas A, Smirnov A, Gražulis S, Ladbury JE, Matulis D
Q Rev Biophys · 2018 Jan · PMID 30912486 · Publisher ↗
The aim of rational drug design is to develop small molecules using a quantitative approach to optimize affinity. This should enhance the development of chemical compounds that would specifically, selectively, reversibly...
The aim of rational drug design is to develop small molecules using a quantitative approach to optimize affinity. This should enhance the development of chemical compounds that would specifically, selectively, reversibly, and with high affinity interact with a target protein. It is not yet possible to develop such compounds using computational (i.e., in silico) approach and instead the lead molecules are discovered in high-throughput screening searches of large compound libraries. The main reason why in silico methods are not capable to deliver is our poor understanding of the compound structure-thermodynamics and structure-kinetics correlations. There is a need for databases of intrinsic binding parameters (e.g., the change upon binding in standard Gibbs energy (ΔGint), enthalpy (ΔHint), entropy (ΔSint), volume (ΔVintr), heat capacity (ΔCp,int), association rate (ka,int), and dissociation rate (kd,int)) between a series of closely related proteins and a chemically diverse, but pharmacophoric group-guided library of compounds together with the co-crystal structures that could help explain the structure-energetics correlations and rationally design novel compounds. Assembly of these data will facilitate attempts to provide correlations and train data for modeling of compound binding. Here, we report large datasets of the intrinsic thermodynamic and kinetic data including over 400 primary sulfonamide compound binding to a family of 12 catalytically active human carbonic anhydrases (CA). Thermodynamic parameters have been determined by the fluorescent thermal shift assay, isothermal titration calorimetry, and by the stopped-flow assay of the inhibition of enzymatic activity. Kinetic measurements were performed using surface plasmon resonance. Intrinsic thermodynamic and kinetic parameters of binding were determined by dissecting the binding-linked protonation reactions of the protein and sulfonamide. The compound structure-thermodynamics and kinetics correlations reported here helped to discover compounds that exhibited picomolar affinities, hour-long residence times, and million-fold selectivities over non-target CA isoforms. Drug-lead compounds are suggested for anticancer target CA IX and CA XII, antiglaucoma CA IV, antiobesity CA VA and CA VB, and other isoforms. Together with 85 X-ray crystallographic structures of 60 compounds bound to six CA isoforms, the database should be of help to continue developing the principles of rational target-based drug design.
Anticipating innovations in structural biology.
Berman HM, Lawson CL, Vallat B … +1 more , Gabanyi MJ
Q Rev Biophys · 2018 Jan · PMID 30912485 · Full text
In this review, we describe how the interplay among science, technology and community interests contributed to the evolution of four structural biology data resources. We present the method by which data deposited by sci...
In this review, we describe how the interplay among science, technology and community interests contributed to the evolution of four structural biology data resources. We present the method by which data deposited by scientists are prepared for worldwide distribution, and argue that data archiving in a trusted repository must be an integral part of any scientific investigation.
DNA partitions into triplets under tension in the presence of organic cations, with sequence evolutionary age predicting the stability of the triplet phase.
Taghavi A, van der Schoot P, Berryman JT
Q Rev Biophys · 2017 Jan · PMID 29233227 · Publisher ↗
Using atomistic simulations, we show the formation of stable triplet structure when particular GC-rich DNA duplexes are extended in solution over a timescale of hundreds of nanoseconds, in the presence of organic salt. W...
Using atomistic simulations, we show the formation of stable triplet structure when particular GC-rich DNA duplexes are extended in solution over a timescale of hundreds of nanoseconds, in the presence of organic salt. We present planar-stacked triplet disproportionated DNA (Σ DNA) as a possible solution phase of the double helix under tension, subject to sequence and the presence of stabilising co-factors. Considering the partitioning of the duplexes into triplets of base pairs as the first step of operation of recombinase enzymes like RecA, we emphasise the structure-function relationship in Σ DNA. We supplement atomistic calculations with thermodynamic arguments to show that codons for 'phase 1' amino acids (those appearing early in evolution) are more likely than a lower entropy GC-rich sequence to form triplets under tension. We further observe that the four amino acids supposed (in the 'GADV world' hypothesis) to constitute the minimal set to produce functional globular proteins have the strongest triplet-forming propensity within the phase 1 set, showing a series of decreasing triplet propensity with evolutionary newness. The weak form of our observation provides a physical mechanism to minimise read frame and recombination alignment errors in the early evolution of the genetic code.
What can be learned about the enzyme ATPase from single-molecule studies of its subunit F1?
Volkán-Kacso S, Marcus RA
Q Rev Biophys · 2017 Jan · PMID 29233226 · Publisher ↗
We summarize the different types of single molecule experiments on the F1 component of FOF1-ATP Synthase and what has been learned from them. We also describe results from our recent studies on interpreting the experimen...
We summarize the different types of single molecule experiments on the F1 component of FOF1-ATP Synthase and what has been learned from them. We also describe results from our recent studies on interpreting the experiments using a chemical-mechanical theory for these biological motors.
Photosynthetic water splitting by the Mn4Ca2+OX catalyst of photosystem II: its structure, robustness and mechanism.
Barber J
Q Rev Biophys · 2017 Jan · PMID 29233225 · Publisher ↗
The biological energy cycle of our planet is driven by photosynthesis whereby sunlight is absorbed by chlorophyll and other accessory pigments. The excitation energy is then efficiently transferred to a reaction centre w...
The biological energy cycle of our planet is driven by photosynthesis whereby sunlight is absorbed by chlorophyll and other accessory pigments. The excitation energy is then efficiently transferred to a reaction centre where charge separation occurs in a few picoseconds. In the case of photosystem II (PSII), the energy of the charge transfer state is used to split water into oxygen and reducing equivalents. This is accomplished by the relatively low energy content of four photons of visible light. PSII is a large multi-subunit membrane protein complex embedded in the lipid environment of the thylakoid membranes of plants, algae and cyanobacteria. Four high energy electrons, together with four protons (4H+), are used to reduce plastoquinone (PQ), the terminal electron acceptor of PSII, to plastoquinol (PQH2). PQH2 passes its reducing equivalents to an electron transfer chain which feeds into photosystem I (PSI) where they gain additional reducing potential from a second light reaction which is necessary to drive CO2 reduction. The catalytic centre of PSII consists of a cluster of four Mn ions and a Ca2+ linked by oxo bonds. In addition, there are seven amino acid ligands. In this Article, I discuss the structure of this metal cluster, its stability and the probability that an acid-base (nucleophilic-electrophilic) mechanism catalyses the water splitting reaction on the surface of the metal-cluster. Evidence for this mechanism is presented from studies on water splitting catalysts consisting of organo-complexes of ruthenium and manganese and also by comparison with the enzymology of carbon monoxide dehydrogenase (CODH). Finally the relevance of our understanding of PSII is discussed in terms of artificial photosynthesis with emphasis on inorganic water splitting catalysts as oxygen generating photoelectrodes.
Ribosome structural dynamics in translocation: yet another functional role for ribosomal RNA.
Noller HF, Lancaster L, Mohan S … +1 more , Zhou J
Q Rev Biophys · 2017 Jan · PMID 29233224 · Publisher ↗
Ribosomes are remarkable ribonucleoprotein complexes that are responsible for protein synthesis in all forms of life. They polymerize polypeptide chains programmed by nucleotide sequences in messenger RNA in a mechanism...
Ribosomes are remarkable ribonucleoprotein complexes that are responsible for protein synthesis in all forms of life. They polymerize polypeptide chains programmed by nucleotide sequences in messenger RNA in a mechanism mediated by transfer RNA. One of the most challenging problems in the ribosome field is to understand the mechanism of coupled translocation of mRNA and tRNA during the elongation phase of protein synthesis. In recent years, the results of structural, biophysical and biochemical studies have provided extensive evidence that translocation is based on the structural dynamics of the ribosome itself. Detailed structural analysis has shown that ribosome dynamics, like aminoacyl-tRNA selection and catalysis of peptide bond formation, is made possible by the properties of ribosomal RNA.
A stretched conformation of DNA with a biological role?
Bosaeus N, Reymer A, Beke-Somfai T … +5 more , Brown T, Takahashi M, Wittung-Stafshede P, Rocha S, Nordén B
Q Rev Biophys · 2017 Jan · PMID 29233223 · Publisher ↗
We have discovered a well-defined extended conformation of double-stranded DNA, which we call Σ-DNA, using laser-tweezers force-spectroscopy experiments. At a transition force corresponding to free energy change ΔG = 1·5...
We have discovered a well-defined extended conformation of double-stranded DNA, which we call Σ-DNA, using laser-tweezers force-spectroscopy experiments. At a transition force corresponding to free energy change ΔG = 1·57 ± 0·12 kcal (mol base pair)-1 60 or 122 base-pair long synthetic GC-rich sequences, when pulled by the 3'-3' strands, undergo a sharp transition to the 1·52 ± 0·04 times longer Σ-DNA. Intriguingly, the same degree of extension is also found in DNA complexes with recombinase proteins, such as bacterial RecA and eukaryotic Rad51. Despite vital importance to all biological organisms for survival, genome maintenance and evolution, the recombination reaction is not yet understood at atomic level. We here propose that the structural distortion represented by Σ-DNA, which is thus physically inherent to the nucleic acid, is related to how recombination proteins mediate recognition of sequence homology and execute strand exchange. Our hypothesis is that a homogeneously stretched DNA undergoes a 'disproportionation' into an inhomogeneous Σ-form consisting of triplets of locally B-like perpendicularly stacked bases. This structure may ensure improved fidelity of base-pair recognition and promote rejection in case of mismatch during homologous recombination reaction. Because a triplet is the length of a gene codon, we speculate that the structural physics of nucleic acids may have biased the evolution of recombinase proteins to exploit triplet base stacks and also the genetic code.
Understanding membrane-active antimicrobial peptides.
Huang HW, Charron NE
Q Rev Biophys · 2017 Jan · PMID 29233222 · Publisher ↗
Bacterial membranes represent an attractive target for the design of new antibiotics to combat widespread bacterial resistance to traditional inhibitor-based antibiotics. Understanding how antimicrobial peptides (AMPs) a...
Bacterial membranes represent an attractive target for the design of new antibiotics to combat widespread bacterial resistance to traditional inhibitor-based antibiotics. Understanding how antimicrobial peptides (AMPs) and other membrane-active agents attack membranes could facilitate the design of new, effective antimicrobials. AMPs, which are small, gene-encoded host defense proteins, offer a promising basis for the study of membrane-active antimicrobial agents. These peptides are cationic and amphipathic, spontaneously binding to bacterial membranes and inducing transmembrane permeability to small molecules. Yet there are often confusions surrounding the details of the molecular mechanisms of AMPs. Following the doctrine of structure-function relationship, AMPs are often viewed as the molecular scaffolding of pores in membranes. Instead we believe that the full mechanism of AMPs is understandable if we consider the interactions of AMPs with the whole membrane domain, where interactions induce structural transformations of the entire membrane, rather than forming localized molecular structures. We believe that it is necessary to consider the entire soft matter peptide-membrane system as it evolves through several distinct states. Accordingly, we have developed experimental techniques to investigate the state and structure of the membrane as a function of the bound peptide to lipid ratio, exactly as AMPs in solution progressively bind to the membrane and induce structural changes to the entire system. The results from these studies suggest that global interactions of AMPs with the membrane domain are of fundamental importance to understanding the antimicrobial mechanisms of AMPs.
Lysozyme's lectin-like characteristics facilitates its immune defense function.
Zhang R, Wu L, Eckert T … +16 more , Burg-Roderfeld M, Rojas-Macias MA, Lütteke T, Krylov VB, Argunov DA, Datta A, Markart P, Guenther A, Norden B, Schauer R, Bhunia A, Enani MA, Billeter M, Scheidig AJ, Nifantiev NE, Siebert HC
Q Rev Biophys · 2017 Jan · PMID 29233221 · Publisher ↗
Interactions between human lysozyme (HL) and the lipopolysaccharide (LPS) of Klebsiella pneumoniae O1, a causative agent of lung infection, were identified by surface plasmon resonance. To characterize the molecular mech...
Interactions between human lysozyme (HL) and the lipopolysaccharide (LPS) of Klebsiella pneumoniae O1, a causative agent of lung infection, were identified by surface plasmon resonance. To characterize the molecular mechanism of this interaction, HL binding to synthetic disaccharides and tetrasaccharides representing one and two repeating units, respectively, of the O-chain of this LPS were studied. pH-dependent structural rearrangements of HL after interaction with the disaccharide were observed through nuclear magnetic resonance. The crystal structure of the HL-tetrasaccharide complex revealed carbohydrate chain packing into the A, B, C, and D binding sites of HL, which primarily occurred through residue-specific, direct or water-mediated hydrogen bonds and hydrophobic contacts. Overall, these results support a crucial role of the Glu35/Asp53/Trp63/Asp102 residues in HL binding to the tetrasaccharide. These observations suggest an unknown glycan-guided mechanism that underlies recognition of the bacterial cell wall by lysozyme and may complement the HL immune defense function.
A new paradigm for atomically detailed simulations of kinetics in biophysical systems.
Elber R
Q Rev Biophys · 2017 Jan · PMID 29233220 · Publisher ↗
The kinetics of biochemical and biophysical events determined the course of life processes and attracted considerable interest and research. For example, modeling of biological networks and cellular responses relies on t...
The kinetics of biochemical and biophysical events determined the course of life processes and attracted considerable interest and research. For example, modeling of biological networks and cellular responses relies on the availability of information on rate coefficients. Atomically detailed simulations hold the promise of supplementing experimental data to obtain a more complete kinetic picture. However, simulations at biological time scales are challenging. Typical computer resources are insufficient to provide the ensemble of trajectories at the correct length that is required for straightforward calculations of time scales. In the last years, new technologies emerged that make atomically detailed simulations of rate coefficients possible. Instead of computing complete trajectories from reactants to products, these approaches launch a large number of short trajectories at different positions. Since the trajectories are short, they are computed trivially in parallel on modern computer architecture. The starting and termination positions of the short trajectories are chosen, following statistical mechanics theory, to enhance efficiency. These trajectories are analyzed. The analysis produces accurate estimates of time scales as long as hours. The theory of Milestoning that exploits the use of short trajectories is discussed, and several applications are described.
A molecular engineering toolbox for the structural biologist.
Debelouchina GT, Muir TW
Q Rev Biophys · 2017 Jan · PMID 29233219 · Full text
Exciting new technological developments have pushed the boundaries of structural biology, and have enabled studies of biological macromolecules and assemblies that would have been unthinkable not long ago. Yet, the enhan...
Exciting new technological developments have pushed the boundaries of structural biology, and have enabled studies of biological macromolecules and assemblies that would have been unthinkable not long ago. Yet, the enhanced capabilities of structural biologists to pry into the complex molecular world have also placed new demands on the abilities of protein engineers to reproduce this complexity into the test tube. With this challenge in mind, we review the contents of the modern molecular engineering toolbox that allow the manipulation of proteins in a site-specific and chemically well-defined fashion. Thus, we cover concepts related to the modification of cysteines and other natural amino acids, native chemical ligation, intein and sortase-based approaches, amber suppression, as well as chemical and enzymatic bio-conjugation strategies. We also describe how these tools can be used to aid methodology development in X-ray crystallography, nuclear magnetic resonance, cryo-electron microscopy and in the studies of dynamic interactions. It is our hope that this monograph will inspire structural biologists and protein engineers alike to apply these tools to novel systems, and to enhance and broaden their scope to meet the outstanding challenges in understanding the molecular basis of cellular processes and disease.
Secondary nucleation of monomers on fibril surface dominates α-synuclein aggregation and provides autocatalytic amyloid amplification.
Gaspar R, Meisl G, Buell AK … +5 more , Young L, Kaminski CF, Knowles TPJ, Sparr E, Linse S
Q Rev Biophys · 2017 Jan · PMID 29233218 · Publisher ↗
Parkinson's disease (PD) is characterized by proteinaceous aggregates named Lewy Bodies and Lewy Neurites containing α-synuclein fibrils. The underlying aggregation mechanism of this protein is dominated by a secondary p...
Parkinson's disease (PD) is characterized by proteinaceous aggregates named Lewy Bodies and Lewy Neurites containing α-synuclein fibrils. The underlying aggregation mechanism of this protein is dominated by a secondary process at mildly acidic pH, as in endosomes and other organelles. This effect manifests as a strong acceleration of the aggregation in the presence of seeds and a weak dependence of the aggregation rate on monomer concentration. The molecular mechanism underlying this process could be nucleation of monomers on fibril surfaces or fibril fragmentation. Here, we aim to distinguish between these mechanisms. The nature of the secondary processes was investigated using differential sedimentation analysis, trap and seed experiments, quartz crystal microbalance experiments and super-resolution microscopy. The results identify secondary nucleation of monomers on the fibril surface as the dominant secondary process leading to rapid generation of new aggregates, while no significant contribution from fragmentation was found. The newly generated oligomeric species quickly elongate to further serve as templates for secondary nucleation and this may have important implications in the spreading of PD.
Chromatin-remodeling for transcription.
Lorch Y, Kornberg RD
Q Rev Biophys · 2017 Jan · PMID 29233217 · Publisher ↗
The nucleosome serves as a general gene repressor, preventing all initiation of transcription except that which is brought about by specific positive regulatory mechanisms. The positive mechanisms begin with chromatin-re...
The nucleosome serves as a general gene repressor, preventing all initiation of transcription except that which is brought about by specific positive regulatory mechanisms. The positive mechanisms begin with chromatin-remodeling by complexes that slide, disrupt, or otherwise alter the structure and organization of nucleosomes. RSC in yeast and its counterpart PBAF in human cells are the major remodeling complexes for transcription. RSC creates a nucleosome-free region in front of a gene, flanked by strongly positioned +1 and -1 nucleosomes, with the transcription start site typically 10-15 bp inside the border of the +1 nucleosome. RSC also binds stably to nucleosomes harboring regulatory elements and to +1 nucleosomes, perturbing their structures in a manner that partially exposes their DNA sequences. The cryo-electron microscope structure of a RSC-nucleosome complex reveals such a structural perturbation, with the DNA largely unwrapped from the nucleosome and likely interacting with a positively charged surface of RSC. Such unwrapping both exposes the DNA and enables its translocation across the histone octamer of the nucleosome by an ATP-dependent activity of RSC. Genetic studies have revealed additional roles of RSC in DNA repair, chromosome segregation, and other chromosomal DNA transactions. These functions of RSC likely involve the same fundamental activities, DNA unwrapping and DNA translocation.
Nucleic acids: function and potential for abiogenesis.
Wachowius F, Attwater J, Holliger P
Q Rev Biophys · 2017 Jan · PMID 29233216 · Publisher ↗
The emergence of functional cooperation between the three main classes of biomolecules - nucleic acids, peptides and lipids - defines life at the molecular level. However, how such mutually interdependent molecular syste...
The emergence of functional cooperation between the three main classes of biomolecules - nucleic acids, peptides and lipids - defines life at the molecular level. However, how such mutually interdependent molecular systems emerged from prebiotic chemistry remains a mystery. A key hypothesis, formulated by Crick, Orgel and Woese over 40 year ago, posits that early life must have been simpler. Specifically, it proposed that an early primordial biology lacked proteins and DNA but instead relied on RNA as the key biopolymer responsible not just for genetic information storage and propagation, but also for catalysis, i.e. metabolism. Indeed, there is compelling evidence for such an 'RNA world', notably in the structure of the ribosome as a likely molecular fossil from that time. Nevertheless, one might justifiably ask whether RNA alone would be up to the task. From a purely chemical perspective, RNA is a molecule of rather uniform composition with all four bases comprising organic heterocycles of similar size and comparable polarity and pK a values. Thus, RNA molecules cover a much narrower range of steric, electronic and physicochemical properties than, e.g. the 20 amino acid side-chains of proteins. Herein we will examine the functional potential of RNA (and other nucleic acids) with respect to self-replication, catalysis and assembly into simple protocellular entities.
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