Dominant mutations in five tRNA synthetases cause Charcot–Marie–Tooth (CMT) neuropathy, suggesting that altered aminoacylation function underlies the disease. However, previous studies showed that loss of aminoacylation activity is not required to cause CMT. Here we present a Drosophila model for CMT with mutations in glycyl-tRNA synthetase (GARS). Expression of three CMT-mutant GARS proteins induces defects in motor performance and motor and sensory neuron morphology, and shortens lifespan. Mutant GARS proteins display normal subcellular localization but markedly reduce global protein synthesis in motor and sensory neurons, or when ubiquitously expressed in adults, as revealed by FUNCAT and BONCAT. Translational slowdown is not attributable to altered tRNAGly aminoacylation, and cannot be rescued by Drosophila Gars overexpression, indicating a gain-of-toxic-function mechanism. Expression of CMT-mutant tyrosyl-tRNA synthetase also impairs translation, suggesting a common pathogenic mechanism. Finally, genetic reduction of translation is sufficient to induce CMT-like phenotypes, indicating a causal contribution of translational slowdown to CMT.

No abstract

Symmetric and asymmetric dimethylation of arginine are isomeric protein posttranslational modifications with distinct biological effects, evidenced by the methylation of arginine 3 of histone H4 (H4R3): symmetric dimethylation of H4R3 leads to repression of gene expression, while asymmetric dimethylation of H4R3 is associated with gene activation. The enzymes catalyzing these modifications share identifiable sequence similarities, but the relationship between their catalytic mechanisms is unknown. Here we analyzed the structure of a prototypic symmetric arginine dimethylase, PRMT5, and discovered that a conserved phenylalanine in the active site is critical for specifying symmetric addition of methyl groups. Changing it to a methionine significantly elevates the overall methylase activity, but also converts PRMT5 to an enzyme that catalyzes both symmetric and asymmetric dimethylation of arginine. Our results demonstrate a common catalytic mechanism intrinsic to both symmetric and asymmetric arginine dimethylases, and show that steric constrains in the active sites play an essential role in determining the product specificity of arginine methylases. This discovery also implies a potentially regulatable outcome of arginine dimethylation that may provide versatile control of eukaryotic gene expression.histone methylation | transtriptional regulation | RNA splicing | crystal structure P rotein arginine methyltransferase 5 (PRMT5) catalyzes the evenly addition of two methyl groups to the two ω-guanidino nitrogen atoms of arginine, resulting in ω-N G , N 0G symmetric dimethylation of arginine (sDMA) of the target protein (1-5). PRMT5 functions in the nucleus as well as in the cytoplasm, and its substrates include histones, spliceosomal proteins, transcription factors, and proteins involved in piRNA biogenesis (6). Symmetric dimethylation of these proteins profoundly impact many biological processes; e.g., epigenetic control of gene expression (7), splicing regulation (2,3,8,9), circadian rhythms (9, 10), DNA damage response (11, 12), and germ cell development and pluripotency (13-16). Interestingly, both PRMT5 and a group of asymmetric (type-I) arginine dimethylases, which add two methyl groups to the same ω-guanidino nitrogen atom (aDMA), share common recognition sequences, and the target arginine can often be symmetrically or asymmetrically dimethylated. Yet, these isomeric modifications have distinct biological effects. One such example occurs at arginine-3 of histone H4 (H4R3). Symmetric dimethylation of H4R3 has been linked to repression of gene expression (17-19), while asymmetric dimethylation of H4R3 is associated with gene activation (20, 21). The startling difference in biological effects of sDMA and aDMA modifications necessitates the understanding of the enzymatic mechanisms differentiating the two chemically isomeric but functionally antagonistic posttranslational modifications. ResultsOverall Structure. We have determined the crystal structures of full-length PRMT5 from Caenorhabditis elegans, alone and ...

[1] Land surface hydrological modeling is sensitive to near-surface air temperature, which is especially true for the cryosphere. The lapse rate of near-surface air temperature is a critical parameter when interpolating air temperature from station data to gridded cells. To obtain spatially distributed, fine-resolution near-surface (2 m) air temperature in the mainland China, monthly air temperature from 553 Chinese national meteorological stations (with continuous data from 1962 to 2011) are divided into 24 regional groups to analyze spatiotemporal variations of lapse rate in relation to surface air temperature and relative humidity. The results are as follows: (1) Evaluation of estimated lapse rate shows that the estimates are reasonable and useful for temperature-related analyses and modeling studies. (2) Lapse rates generally have a banded spatial distribution from southeast to northwest, with relatively large values on the Tibetan Plateau and in northeast China. The greatest spatial variability is in winter with a range of 0.3°C-0.9°C · 100 m À1 , accompanied by an inversion phenomenon in the northern Xinjiang Province. In addition, the lapse rates show a clear seasonal cycle. (3) The lapse rates maintain a consistently positive correlation with temperature in all seasons, and these correlations are more prevalent in the north and east. The lapse rates exhibit a negative relationship with relative humidity in all seasons, especially in the east. (4) Substantial regional differences in temporal lapse rate trends over the study period are identified. Increasing lapse rates are more pronounced in northern China, and decreasing trends are found in southwest China, which are more notable in winter. An overall increase of air temperature and regional variation of relative humidity together influenced the change of lapse rate.

Snow and frozen soil are important factors that influence terrestrial water and energy balances through snowpack accumulation and melt and soil freeze-thaw. In this study, a new land surface model (LSM) with coupled snow and frozen soil physics was developed based on a hydrologically improved LSM (HydroSiB2). First, an energy-balance-based three-layer snow model was incorporated into HydroSiB2 (hereafter HydroSiB2-S) to provide an improved description of the internal processes of the snow pack. Second, a universal and simplified soil model was coupled with HydroSiB2-S to depict soil water freezing and thawing (hereafter HydroSiB2-SF). In order to avoid the instability caused by the uncertainty in estimating water phase changes, enthalpy was adopted as a prognostic variable instead of snow/soil temperature in the energy balance equation of the snow/frozen soil module. The newly developed models were then carefully evaluated at two typical sites of the Tibetan Plateau (TP) (one snow covered and the other snow free, both with underlying frozen soil). At the snow-covered site in northeastern TP (DY), HydroSiB2-SF demonstrated significant improvements over HydroSiB2-F (same as HydroSiB2-SF but using the original single-layer snow module of HydroSiB2), showing the importance of snow internal processes in three-layer snow parameterization. At the snow-free site in southwestern TP (Ngari), HydroSiB2-SF reasonably simulated soil water phase changes while HydroSiB2-S did not, indicating the crucial role of frozen soil parameterization in depicting the soil thermal and water dynamics. Finally, HydroSiB2-SF proved to be capable of simulating upward moisture fluxes toward the freezing front from the underlying soil layers in winter.

No abstract

Maintenance of the Golgi apparatus (GA) structure and function depends on Golgi matrix proteins. The posttranslational modification of Golgi proteins such as phosphorylation of members of the golgin and GRASP families is important for determining Golgi architecture. Some Golgi proteins including golgin-84 are also known to be methylated, but the function of golgin methylation remains unclear. Here, we show that the protein arginine methyltransferase 5 (PRMT5) localizes to the GA and forms complexes with several components involved in GA ribbon formation and vesicle tethering. PRMT5 interacts with the golgin GM130, and depletion of PRMT5 causes defects in Golgi ribbon formation. Furthermore, PRMT5 methylates N-terminal arginines in GM130, and such arginine methylation appears critical for GA ribbon formation. Our findings reveal a molecular mechanism by which PRMT5-dependent arginine methylation of GM130 controls the maintenance of GA architecture.

In distributed hydrological modeling, surface air temperature (Tair) is of great importance in simulating cold region processes, while the near‐surface‐air‐temperature lapse rate (NLR) is crucial to prepare Tair (when interpolating Tair from site observations to model grids). In this study, a distributed biosphere hydrological model with improved snow physics (WEB‐DHM‐S) was rigorously evaluated in a typical cold, large river basin (e.g., the upper Yellow River basin), given a mean monthly NLRs. Based on the validated model, we have examined the influence of the NLR on the simulated snow processes and streamflows. We found that the NLR has a large effect on the simulated streamflows, with a maximum difference of greater than 24% among the various scenarios for NLRs considered. To supplement the insufficient number of monitoring sites for near‐surface‐air‐temperature at developing/undeveloped mountain regions, the nighttime Moderate Resolution Imaging Spectroradiometer land surface temperature is used as an alternative to derive the approximate NLR at a finer spatial scale (e.g., at different elevation bands, different land covers, different aspects, and different snow conditions). Using satellite‐based estimation of NLR, the modeling of snow processes has been greatly refined. Results show that both the determination of rainfall/snowfall and the snowpack process were significantly improved, contributing to a reduced summer evapotranspiration and thus an improved streamflow simulation.