{"title":"The biophysics of superoxide dismutase-1 and amyotrophic lateral sclerosis","authors":"G. Wright, S. Antonyuk, S. Hasnain","doi":"10.1017/S003358351900012X","DOIUrl":"https://doi.org/10.1017/S003358351900012X","url":null,"abstract":"Abstract Few proteins have come under such intense scrutiny as superoxide dismutase-1 (SOD1). For almost a century, scientists have dissected its form, function and then later its malfunction in the neurodegenerative disease amyotrophic lateral sclerosis (ALS). We now know SOD1 is a zinc and copper metalloenzyme that clears superoxide as part of our antioxidant defence and respiratory regulation systems. The possibility of reduced structural integrity was suggested by the first crystal structures of human SOD1 even before deleterious mutations in the sod1 gene were linked to the ALS. This concept evolved in the intervening years as an impressive array of biophysical studies examined the characteristics of mutant SOD1 in great detail. We now recognise how ALS-related mutations perturb the SOD1 maturation processes, reduce its ability to fold and reduce its thermal stability and half-life. Mutant SOD1 is therefore predisposed to monomerisation, non-canonical self-interactions, the formation of small misfolded oligomers and ultimately accumulation in the tell-tale insoluble inclusions found within the neurons of ALS patients. We have also seen that several post-translational modifications could push wild-type SOD1 down this toxic pathway. Recently we have come to view ALS as a prion-like disease where both the symptoms, and indeed SOD1 misfolding itself, are transmitted to neighbouring cells. This raises the possibility of intervention after the initial disease presentation. Several small-molecule and biologic-based strategies have been devised which directly target the SOD1 molecule to change the behaviour thought to be responsible for ALS. Here we provide a comprehensive review of the many biophysical advances that sculpted our view of SOD1 biology and the recent work that aims to apply this knowledge for therapeutic outcomes in ALS.","PeriodicalId":20828,"journal":{"name":"Quarterly Reviews of Biophysics","volume":"56 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2019-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76195250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The behavior of ions in water is controlled by their water affinity","authors":"K. D. Collins","doi":"10.1017/S0033583519000106","DOIUrl":"https://doi.org/10.1017/S0033583519000106","url":null,"abstract":"Abstract The strong, long-range electrostatic forces described by Coulomb's law disappear for ions in water, and the behavior of these ions is instead controlled by their water affinity – a weak, short-range force which arises from their charge density. This was established experimentally in the mid-1980s by size-exclusion chromatography on carefully calibrated Sephadex® G-10 (which measures the effective volume and thus the water affinity of an ion) and by neutron diffraction with isotopic substitution (which measures the density and orientation of water molecules near the diffracting ion and thus its water affinity). These conclusions have been confirmed more recently by molecular dynamics simulations, which explicitly model each individual water molecule. This surprising change in force regime occurs because the oppositely charged ions in aqueous salt solutions exist functionally as ion pairs (separated by 0, 1 or 2 water molecules) as has now been shown by dielectric relaxation spectroscopy; this cancels out the strong long-range electrostatic forces and allows the weak, short-range water affinity effects to come to the fore. This microscopic structure of aqueous salt solutions is not captured by models utilizing a macroscopic dielectric constant. Additionally, the Law of Matching Water Affinity, first described in 1997 and 2004, establishes that contact ion pair formation is controlled by water affinity and is a major determinant of the solubility of charged species since only a net neutral species can change phases.","PeriodicalId":20828,"journal":{"name":"Quarterly Reviews of Biophysics","volume":"134 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2019-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77387029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
C. Gahmberg, M. Grönholm, Sudarrshan Madhavan, Farhana Jahan, Esa T Mikkola, Larisa Viazmina, E. Koivunen
{"title":"Regulation of cell adhesion: a collaborative effort of integrins, their ligands, cytoplasmic actors, and phosphorylation","authors":"C. Gahmberg, M. Grönholm, Sudarrshan Madhavan, Farhana Jahan, Esa T Mikkola, Larisa Viazmina, E. Koivunen","doi":"10.1017/S0033583519000088","DOIUrl":"https://doi.org/10.1017/S0033583519000088","url":null,"abstract":"Abstract Integrins are large heterodimeric type 1 membrane proteins expressed in all nucleated mammalian cells. Eighteen α-chains and eight β-chains can combine to form 24 different integrins. They are cell adhesion proteins, which bind to a large variety of cellular and extracellular ligands. Integrins are required for cell migration, hemostasis, translocation of cells out from the blood stream and further movement into tissues, but also for the immune response and tissue morphogenesis. Importantly, integrins are not usually active as such, but need activation to become adhesive. Integrins are activated by outside-in activation through integrin ligand binding, or by inside-out activation through intracellular signaling. An important question is how integrin activity is regulated, and this topic has recently drawn much attention. Changes in integrin affinity for ligand binding are due to allosteric structural alterations, but equally important are avidity changes due to integrin clustering in the plane of the plasma membrane. Recent studies have partially solved how integrin cell surface structures change during activation. The integrin cytoplasmic domains are relatively short, but by interacting with a variety of cytoplasmic proteins in a regulated manner, the integrins acquire a number of properties important not only for cell adhesion and movement, but also for cellular signaling. Recent work has shown that specific integrin phosphorylations play pivotal roles in the regulation of integrin activity. Our purpose in this review is to integrate the present knowledge to enable an understanding of how cell adhesion is dynamically regulated.","PeriodicalId":20828,"journal":{"name":"Quarterly Reviews of Biophysics","volume":"19 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2019-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81772225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hamish G. Hiscock, Tom W. Hiscock, Tom W. Hiscock, D. Kattnig, T. Scrivener, Alan M. Lewis, D. Manolopoulos, P. Hore
{"title":"Navigating at night: fundamental limits on the sensitivity of radical pair magnetoreception under dim light","authors":"Hamish G. Hiscock, Tom W. Hiscock, Tom W. Hiscock, D. Kattnig, T. Scrivener, Alan M. Lewis, D. Manolopoulos, P. Hore","doi":"10.1017/S0033583519000076","DOIUrl":"https://doi.org/10.1017/S0033583519000076","url":null,"abstract":"Abstract Night-migratory songbirds appear to sense the direction of the Earth's magnetic field via radical pair intermediates formed photochemically in cryptochrome flavoproteins contained in photoreceptor cells in their retinas. It is an open question whether this light-dependent mechanism could be sufficiently sensitive given the low-light levels experienced by nocturnal migrants. The scarcity of available photons results in significant uncertainty in the signal generated by the magnetoreceptors distributed around the retina. Here we use results from Information Theory to obtain a lower bound estimate of the precision with which a bird could orient itself using only geomagnetic cues. Our approach bypasses the current lack of knowledge about magnetic signal transduction and processing in vivo by computing the best-case compass precision under conditions where photons are in short supply. We use this method to assess the performance of three plausible cryptochrome-derived flavin-containing radical pairs as potential magnetoreceptors.","PeriodicalId":20828,"journal":{"name":"Quarterly Reviews of Biophysics","volume":"1 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2019-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79743052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Tracking RNA with light: selection, structure, and design of fluorescence turn-on RNA aptamers","authors":"R. Trachman, A. Ferré-D’Amaré","doi":"10.1017/S0033583519000064","DOIUrl":"https://doi.org/10.1017/S0033583519000064","url":null,"abstract":"Abstract Fluorescence turn-on aptamers, in vitro evolved RNA molecules that bind conditional fluorophores and activate their fluorescence, have emerged as RNA counterparts of the fluorescent proteins. Turn-on aptamers have been selected to bind diverse fluorophores, and they achieve varying degrees of specificity and affinity. These RNA–fluorophore complexes, many of which exceed the brightness of green fluorescent protein and their variants, can be used as tags for visualizing RNA localization and transport in live cells. Structure determination of several fluorescent RNAs revealed that they have diverse, unrelated overall architectures. As most of these RNAs activate the fluorescence of their ligands by restraining their photoexcited states into a planar conformation, their fluorophore binding sites have in common a planar arrangement of several nucleobases, most commonly a G-quartet. Nonetheless, each turn-on aptamer has developed idiosyncratic structural solutions to achieve specificity and efficient fluorescence turn-on. The combined structural diversity of fluorophores and turn-on RNA aptamers has already produced combinations that cover the visual spectrum. Further molecular evolution and structure-guided engineering is likely to produce fluorescent tags custom-tailored to specific applications.","PeriodicalId":20828,"journal":{"name":"Quarterly Reviews of Biophysics","volume":"16 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2019-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76492579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M. Grimaldo, F. Roosen‐Runge, Fajun Zhang, F. Schreiber, T. Seydel
{"title":"Dynamics of proteins in solution","authors":"M. Grimaldo, F. Roosen‐Runge, Fajun Zhang, F. Schreiber, T. Seydel","doi":"10.1017/S0033583519000027","DOIUrl":"https://doi.org/10.1017/S0033583519000027","url":null,"abstract":"Abstract The dynamics of proteins in solution includes a variety of processes, such as backbone and side-chain fluctuations, interdomain motions, as well as global rotational and translational (i.e. center of mass) diffusion. Since protein dynamics is related to protein function and essential transport processes, a detailed mechanistic understanding and monitoring of protein dynamics in solution is highly desirable. The hierarchical character of protein dynamics requires experimental tools addressing a broad range of time- and length scales. We discuss how different techniques contribute to a comprehensive picture of protein dynamics, and focus in particular on results from neutron spectroscopy. We outline the underlying principles and review available instrumentation as well as related analysis frameworks.","PeriodicalId":20828,"journal":{"name":"Quarterly Reviews of Biophysics","volume":"105 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2019-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79275017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The theory of frame ordering: observing motions in calmodulin complexes.","authors":"Edward James d'Auvergne, Christian Griesinger","doi":"10.1017/S0033583519000015","DOIUrl":"https://doi.org/10.1017/S0033583519000015","url":null,"abstract":"<p><p>Large scale functional motions of molecules are studied experimentally using numerous molecular and biophysics techniques, the data from which are subsequently interpreted using diverse models of Brownian molecular dynamics. To unify all rotational physics techniques and motional models, the frame order tensor - a universal statistical mechanics theory based on the rotational ordering of rigid body frames - is herein formulated. The frame ordering is the fundamental physics that governs how motions modulate rotational molecular physics and it defines the properties and maximum information content encoded in the observable physics. Using the tensor to link residual dipolar couplings and pseudo-contact shifts, two distinct information-rich and atomic-level biophysical measurements from the field of nuclear magnetic resonance spectroscopy, to a number of basic mechanical joint models, a highly dynamic state of calmodulin (CaM) bound to a target peptide in a tightly closed conformation was observed. Intra- and inter-domain motions reveal the CaM complex to be entropically primed for peptide release.</p>","PeriodicalId":20828,"journal":{"name":"Quarterly Reviews of Biophysics","volume":"52 ","pages":"e3"},"PeriodicalIF":6.1,"publicationDate":"2019-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1017/S0033583519000015","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39897403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Oxygenic photosynthesis: history, status and perspective.","authors":"Wolfgang Junge","doi":"10.1017/S0033583518000112","DOIUrl":"https://doi.org/10.1017/S0033583518000112","url":null,"abstract":"<p><p>Cyanobacteria and plants carry out oxygenic photosynthesis. They use water to generate the atmospheric oxygen we breathe and carbon dioxide to produce the biomass serving as food, feed, fibre and fuel. This paper scans the emergence of structural and mechanistic understanding of oxygen evolution over the past 50 years. It reviews speculative concepts and the stepped insight provided by novel experimental and theoretical techniques. Driven by sunlight photosystem II oxidizes the catalyst of water oxidation, a hetero-metallic Mn4CaO5(H2O)4 cluster. Mn3Ca are arranged in cubanoid and one Mn dangles out. By accumulation of four oxidizing equivalents before initiating dioxygen formation it matches the four-electron chemistry from water to dioxygen to the one-electron chemistry of the photo-sensitizer. Potentially harmful intermediates are thereby occluded in space and time. Kinetic signatures of the catalytic cluster and its partners in the photo-reaction centre have been resolved, in the frequency domain ranging from acoustic waves via infra-red to X-ray radiation, and in the time domain from nano- to milli-seconds. X-ray structures to a resolution of 1.9 Å are available. Even time resolved X-ray structures have been obtained by clocking the reaction cycle by flashes of light and diffraction with femtosecond X-ray pulses. The terminal reaction cascade from two molecules of water to dioxygen involves the transfer of four electrons, two protons, one dioxygen and one water. A rigorous mechanistic analysis is challenging because of the kinetic enslaving at millisecond duration of six partial reactions (4e-, 1H+, 1O2). For the time being a peroxide-intermediate in the reaction cascade to dioxygen has been in focus, both experimentally and by quantum chemistry. Homo sapiens has relied on burning the products of oxygenic photosynthesis, recent and fossil. Mankind's total energy consumption amounts to almost one-fourth of the global photosynthetic productivity. If the average power consumption equalled one of those nations with the highest consumption per capita it was four times greater and matched the total productivity. It is obvious that biomass should be harvested for food, feed, fibre and platform chemicals rather than for fuel.</p>","PeriodicalId":20828,"journal":{"name":"Quarterly Reviews of Biophysics","volume":"52 ","pages":"e1"},"PeriodicalIF":6.1,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1017/S0033583518000112","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36887204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Development of CRISPR-Cas systems for genome editing and beyond","authors":"F. Zhang","doi":"10.1017/S0033583519000052","DOIUrl":"https://doi.org/10.1017/S0033583519000052","url":null,"abstract":"Abstract The development of clustered regularly interspaced short-palindromic repeat (CRISPR)-Cas systems for genome editing has transformed the way life science research is conducted and holds enormous potential for the treatment of disease as well as for many aspects of biotechnology. Here, I provide a personal perspective on the development of CRISPR-Cas9 for genome editing within the broader context of the field and discuss our work to discover novel Cas effectors and develop them into additional molecular tools. The initial demonstration of Cas9-mediated genome editing launched the development of many other technologies, enabled new lines of biological inquiry, and motivated a deeper examination of natural CRISPR-Cas systems, including the discovery of new types of CRISPR-Cas systems. These new discoveries in turn spurred further technological developments. I review these exciting discoveries and technologies as well as provide an overview of the broad array of applications of these technologies in basic research and in the improvement of human health. It is clear that we are only just beginning to unravel the potential within microbial diversity, and it is quite likely that we will continue to discover other exciting phenomena, some of which it may be possible to repurpose as molecular technologies. The transformation of mysterious natural phenomena to powerful tools, however, takes a collective effort to discover, characterize, and engineer them, and it has been a privilege to join the numerous researchers who have contributed to this transformation of CRISPR-Cas systems.","PeriodicalId":20828,"journal":{"name":"Quarterly Reviews of Biophysics","volume":"4 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79199023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Controlling the movement of molecules","authors":"R. Langer","doi":"10.1017/S0033583519000040","DOIUrl":"https://doi.org/10.1017/S0033583519000040","url":null,"abstract":"Abstract The ability to control the movement of molecules is both fascinating scientifically as well as being critically important to the well-being of our planet and its people. In particular, the sustained release of molecules over prolonged periods at controlled rates has had and will continue to have enormous implications for the delivery of substances in medicine, agriculture, the environment, nutrition, aquaculture, household consumer products, and numerous other areas. This field is advancing at a rapidly accelerating pace. In this article, I largely discuss our own work, starting 45 years ago, in enabling the controlled release of macromolecules from biocompatible polymers. I also discuss the synthesis of novel materials to affect molecular movement and I then examine external approaches for controlling the movement of molecules through materials, using forces such as electric, acoustic, and magnetic fields. I further discuss approaches for controlling molecular movement through physiologic barriers, such as the skin, lung, and intestine. Finally, I outline several future areas of this field, including how it can affect the developing world, the ability to control the movement of molecules into mammalian cells, and the design of intelligent approaches to control molecular delivery.","PeriodicalId":20828,"journal":{"name":"Quarterly Reviews of Biophysics","volume":"38 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75940725","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}