Biophysical and structural analysis of KRAS switch-II pocket inhibitors reveals allele-specific binding constraints
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Biochemistry & Molecular Biology↗
Engineering topics
Alexander, Patrick
Publications and source records attributed to Alexander, Patrick.
Structure of the SHOC2?MRAS?PP1C complex provides insights into RAF activation and Noonan syndrome
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Bonsor, Daniel A.↗
Projected land ice contributions to twenty-first-century sea level rise
The land ice contribution to global mean sea level rise has not yet been predicted using ice sheet and glacier models for the latest set of socio-economic scenarios, nor using coordinated exploration of uncertainties arising from the various computer models involved. Two recent international projects generated a large suite of projections using multiple models, but primarily used previous-generation scenarios and climate models, and could not fully explore known uncertainties. Here we estimate probability distributions for these projections under the new scenarios using statistical emulation of the ice sheet and glacier models. In this work, we find that limiting global warming to 1.5 degrees Celsius would halve the land ice contribution to twenty-first-century sea level rise, relative to current emissions pledges. The median decreases from 25 to 13 centimetres sea level equivalent (SLE) by 2100, with glaciers responsible for half the sea level contribution. The projected Antarctic contribution does not show a clear response to the emissions scenario, owing to uncertainties in the competing processes of increasing ice loss and snowfall accumulation in a warming climate. However, under risk-averse (pessimistic) assumptions, Antarctic ice loss could be five times higher, increasing the median land ice contribution to 42 centimetres SLE under current policies and pledges, with the 95th percentile projection exceeding half a metre even under 1.5 degrees Celsius warming. This would severely limit the possibility of mitigating future coastal flooding. Given this large range (between 13 centimetres SLE using the main projections under 1.5 degrees Celsius warming and 42 centimetres SLE using risk-averse projections under current pledges), adaptation planning for twenty-first-century sea level rise must account for a factor-of-three uncertainty in the land ice contribution until climate policies and the Antarctic response are further constrained.
54 ENVIRONMENTAL SCIENCES↗
Future sea level change under CMIP5 and CMIP6 scenarios from the Greenland and Antarctic ice sheets
Projections of the sea level contribution from the Greenland and Antarctic ice sheets rely on atmospheric and oceanic drivers obtained from climate models. The Earth System Models participating in the Coupled Model Intercomparison Project phase 6 (CMIP6) generally project greater future warming compared with the previous CMIP5 effort. Here we use four CMIP6 models and a selection of CMIP5 models to force multiple ice sheet models as part of the Ice Sheet Model Intercomparison Project for CMIP6 (ISMIP6). We find that the projected sea level contribution at 2100 from the ice sheet model ensemble under the CMIP6 scenarios falls within the CMIP5 range for the Antarctic ice sheet but is significantly increased for Greenland. Warmer atmosphere in CMIP6 models results in higher Greenland mass loss due to surface melt. For Antarctica, CMIP6 forcing is similar to CMIP5 and mass gain from increased snowfall counteracts increased loss due to ocean warming.
54 ENVIRONMENTAL SCIENCES↗
Uncovering a membrane-distal conformation of KRAS available to recruit RAF to the plasma membrane
The small GTPase KRAS is localized at the plasma membrane where it functions as a molecular switch, coupling extracellular growth factor stimulation to intracellular signaling networks. In this process, KRAS recruits effectors, such as RAF kinase, to the plasma membrane where they are activated by a series of complex molecular steps. Defining the membrane-bound state of KRAS is fundamental to understanding the activation of RAF kinase and in evaluating novel therapeutic opportunities for the inhibition of oncogenic KRAS-mediated signaling. We combined multiple biophysical measurements and computational methodologies to generate a consensus model for authentically processed, membrane-anchored KRAS. In contrast to the two membrane-proximal conformations previously reported, we identify a third significantly populated state using a combination of neutron reflectivity, fast photochemical oxidation of proteins (FPOP), and NMR. In this highly populated state, which we refer to as “membrane-distal” and estimate to comprise ~90% of the ensemble, the G-domain does not directly contact the membrane but is tethered via its C-terminal hypervariable region and carboxymethylated farnesyl moiety, as shown by FPOP. Subsequent interaction of the RAF1 RAS binding domain with KRAS does not significantly change G-domain configurations on the membrane but affects their relative populations. Overall, our results are consistent with a directional fly-casting mechanism for KRAS, in which the membrane-distal state of the G-domain can effectively recruit RAF kinase from the cytoplasm for activation at the membrane.
KRAS↗
Experimental protocol for sea level projections from ISMIP6 stand-alone ice sheet models
Projection of the contribution of ice sheets to sea level change as part of the Coupled Model Intercomparison Project Phase 6 (CMIP6) takes the form of simulations from coupled ice sheet–climate models and stand-alone ice sheet models, overseen by the Ice Sheet Model Intercomparison Project for CMIP6 (ISMIP6). This paper describes the experimental setup for process-based sea level change projections to be performed with stand-alone Greenland and Antarctic ice sheet models in the context of ISMIP6. The ISMIP6 protocol relies on a suite of polar atmospheric and oceanic CMIP-based forcing for ice sheet models, in order to explore the uncertainty in projected sea level change due to future emissions scenarios, CMIP models, ice sheet models, and parameterizations for ice–ocean interactions. We describe here the approach taken for defining the suite of ISMIP6 stand-alone ice sheet simulations, document the experimental framework and implementation, and present an overview of the ISMIP6 forcing to be used by participating ice sheet modeling groups.
54 ENVIRONMENTAL SCIENCES↗
The SUMup Dataset: Compiled Measurements of Surface Mass Balance Components over Ice Sheets and Sea Ice with Analysis over Greenland
Increasing atmospheric temperatures over ice cover affect surface processes, including melt, snowfall, and snow density. Here, we present the Surface Mass Balance and Snow on Sea Ice Working Group (SUMup) dataset, a standardized dataset of Arctic and Antarctic observations of surface mass balance components. The July 2018 SUMup dataset consists of three subdatasets, snow/firn density (https://doi.org/10.18739/A2JH3D23R), at least near-annually resolved snow accumulation on land ice (https://doi.org/10.18739/A2DR2P790), and snow depth on sea ice (https://doi.org/10.18739/A2WS8HK6X), to monitor change and improve estimates of surface mass balance. The measurements in this dataset were compiled from field notes, papers, technical reports, and digital files. SUMup is a compiled, community-based dataset that can be and has been used to evaluate modeling efforts and remote sensing retrievals. Active submission of new or past measurements is encouraged. Analysis of the dataset shows that Greenland Ice Sheet density measurements in the top 1m do not show a strong relationship with annual temperature. At Summit Station, Greenland, accumulation and surface density measurements vary seasonally with lower values during summer months. The SUMup dataset is a dynamic, living dataset that will be updated and expanded for community use as new measurements are taken and new processes are discovered and quantified.
Montgomery, Lynn↗
The Darkening of the Greenland Ice Sheet: Trends, Drivers and Projections (1981-2100)
The surface energy balance and meltwater production of the Greenland ice sheet (GrIS) are modulated by snow and ice albedo through the amount of absorbed solar radiation. Here we show, using space-borne multispectral data collected during the 3 decades from 1981 to 2012, that summertime surface albedo over the GrIS decreased at a statistically significant (99 %) rate of 0.02 decade(sup -1) between 1996 and 2012. Over the same period, albedo modelled by the Modele Atmospherique Regionale (MAR) also shows a decrease, though at a lower rate (approximately -0.01 decade(sup -1)) than that obtained from space-borne data. We suggest that the discrepancy between modelled and measured albedo trends can be explained by the absence in the model of processes associated with the presence of light-absorbing impurities. The negative trend in observed albedo is confined to the regions of the GrIS that undergo melting in summer, with the dry snow zone showing no trend. The period 1981-1996 also showed no statistically significant trend over the whole GrIS. Analysis of MAR outputs indicates that the observed albedo decrease is attributable to the combined effects of increased near-surface air temperatures, which enhanced melt and promoted growth in snow grain size and the expansion of bare ice areas, and to trends in light-absorbing impurities (LAI) on the snow and ice surfaces. Neither aerosol models nor in situ and remote sensing observations indicate increasing trends in LAI in the atmosphere over Greenland. Similarly, an analysis of the number of fires and BC emissions from fires points to the absence of trends for such quantities. This suggests that the apparent increase of LAI in snow and ice might be related to the exposure of a "dark band" of dirty ice and to increased consolidation of LAI at the surface with melt, not to increased aerosol deposition. Albedo projections through to the end of the century under different warming scenarios consistently point to continued darkening, with albedo anomalies averaged over the whole ice sheet lower by 0.08 in 2100 than in 2000, driven solely by a warming climate. Future darkening is likely underestimated because of known underestimates in modelled melting (as seen in hindcasts) and because the model albedo scheme does not currently include the effects of LAI, which have a positive feedback on albedo decline through increased melting, grain growth, and darkening.
surface energy↗