406 research outputs found
Structure Modeling of All Identified G Protein–Coupled Receptors in the Human Genome
G protein–coupled receptors (GPCRs), encoded by about 5% of human genes, comprise the largest family of integral membrane proteins and act as cell surface receptors responsible for the transduction of endogenous signal into a cellular response. Although tertiary structural information is crucial for function annotation and drug design, there are few experimentally determined GPCR structures. To address this issue, we employ the recently developed threading assembly refinement (TASSER) method to generate structure predictions for all 907 putative GPCRs in the human genome. Unlike traditional homology modeling approaches, TASSER modeling does not require solved homologous template structures; moreover, it often refines the structures closer to native. These features are essential for the comprehensive modeling of all human GPCRs when close homologous templates are absent. Based on a benchmarked confidence score, approximately 820 predicted models should have the correct folds. The majority of GPCR models share the characteristic seven-transmembrane helix topology, but 45 ORFs are predicted to have different structures. This is due to GPCR fragments that are predominantly from extracellular or intracellular domains as well as database annotation errors. Our preliminary validation includes the automated modeling of bovine rhodopsin, the only solved GPCR in the Protein Data Bank. With homologous templates excluded, the final model built by TASSER has a global C(α) root-mean-squared deviation from native of 4.6 Å, with a root-mean-squared deviation in the transmembrane helix region of 2.1 Å. Models of several representative GPCRs are compared with mutagenesis and affinity labeling data, and consistent agreement is demonstrated. Structure clustering of the predicted models shows that GPCRs with similar structures tend to belong to a similar functional class even when their sequences are diverse. These results demonstrate the usefulness and robustness of the in silico models for GPCR functional analysis. All predicted GPCR models are freely available for noncommercial users on our Web site (http://www.bioinformatics.buffalo.edu/GPCR)
Hearts deficient in both Mfn1 and Mfn2 are protected against acute myocardial infarction
Mitochondria alter their shape by undergoing cycles of fusion and fission. Changes in mitochondrial morphology impact on the cellular response to stress, and their interactions with other organelles such as the sarcoplasmic reticulum (SR). Inhibiting mitochondrial fission can protect the heart against acute ischemia/reperfusion (I/R) injury. However, the role of the mitochondrial fusion proteins, Mfn1 and Mfn2, in the response of the adult heart to acute I/R injury is not clear, and is investigated in this study. To determine the effect of combined Mfn1/Mfn2 ablation on the susceptibility to acute myocardial I/R injury, cardiac-specific ablation of both Mfn1 and Mfn2 (DKO) was initiated in mice aged 4-6 weeks, leading to knockout of both these proteins in 8-10-week-old animals. This resulted in fragmented mitochondria (electron microscopy), decreased mitochondrial respiratory function (respirometry), and impaired myocardial contractile function (echocardiography). In DKO mice subjected to in vivo regional myocardial ischemia (30 min) followed by 24 h reperfusion, myocardial infarct size (IS, expressed as a % of the area-at-risk) was reduced by 46% compared with wild-type (WT) hearts. In addition, mitochondria from DKO animals had decreased MPTP opening susceptibility (assessed by Ca(2+)-induced mitochondrial swelling), compared with WT hearts. Mfn2 is a key mediator of mitochondrial/SR tethering, and accordingly, the loss of Mfn2 in DKO hearts reduced the number of interactions measured between these organelles (quantified by proximal ligation assay), attenuated mitochondrial calcium overload (Rhod2 confocal microscopy), and decreased reactive oxygen species production (DCF confocal microscopy) in response to acute I/R injury. No differences in isolated mitochondrial ROS emissions (Amplex Red) were detected in response to Ca(2+) and Antimycin A, further implicating disruption of mitochondria/SR tethering as the protective mechanism. In summary, despite apparent mitochondrial dysfunction, hearts deficient in both Mfn1 and Mfn2 are protected against acute myocardial infarction due to impaired mitochondria/SR tethering
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ERK1/2 signaling dominates over RhoA signaling in regulating early changes in RNA expression induced by endothelin-1 in neonatal rat cardiomyocytes
Cardiomyocyte hypertrophy is associated with changes in gene expression. Extracellular signal-regulated kinases 1/2 (ERK1/2) and RhoA [activated by hypertrophic agonists (e.g. endothelin-1)] regulate gene expression and are implicated in the response, but their relative significance in regulating the cardiomyocyte transcriptome is unknown. Our aim was to establish the significance of ERK1/2 and/or RhoA in the early cardiomyocyte transcriptomic response to endothelin-1.Cardiomyocytes were exposed to endothelin-1 (1 h) with/without PD184352 (to inhibit ERK1/2) or C3 transferase (C3T, to inhibit RhoA). RNA expression was analyzed using microarrays and qPCR. ERK1/2 signaling positively regulated approximately 65% of the early gene expression response to ET-1 with a small (approximately 2%) negative effect, whereas RhoA signaling positively regulated approximately 10% of the early gene expression response to ET-1 with a greater (approximately 14%) negative contribution. Of RNAs non-responsive to endothelin-1, 66 or 448 were regulated by PD184352 or C3T, respectively, indicating that RhoA had a more significant effect on baseline RNA expression. mRNAs upregulated by endothelin-1 encoded a number of receptor ligands (e.g. Ereg, Areg, Hbegf) and transcription factors (e.g. Abra/Srf) that potentially propagate the response.ERK1/2 dominates over RhoA in the early transcriptomic response to endothelin-1. RhoA plays a major role in maintaining baseline RNA expression but, with upregulation of Abra/Srf by endothelin-1, RhoA may regulate changes in RNA expression over longer times. Our data identify ERK1/2 as a more significant node than RhoA in regulating the early stages of cardiomyocyte hypertrophy
Endothelial g protein-coupled receptor kinase 2 regulates vascular homeostasis through the control of free radical oxygen species.
An exact formula for the radiation of a moving quark in N=4 super Yang Mills
We derive an exact formula for the cusp anomalous dimension at small angles.
This is done by relating the latter to the computation of certain 1/8 BPS
Wilson loops which was performed by supersymmetric localization. This function
of the coupling also determines the power emitted by a moving quark in N=4
super Yang Mills, as well as the coefficient of the two point function of the
displacement operator on the Wilson loop. By a similar method we compute the
near BPS expansion of the generalized cusp anomalous dimension.Comment: 22 pages, 5 figures. v2: references added, typos correcte
G protein-coupled receptor kinase 2 activity impairs cardiac glucose uptake and promotes insulin resistance after myocardial ischemia.
Refined Cigar and Omega-deformed Conifold
Antoniadis et al proposed a relation between the Omega-deformation and
refined correlation functions of the topological string theory. We investigate
the proposal for the deformed conifold geometry from a non-compact Gepner model
approach. The topological string theory on the deformed conifold has a dual
description in terms of the c=1 non-critical string theory at the self-dual
radius, and the Omega-deformation yields the radius deformation. We show that
the refined correlation functions computed from the twisted SL(2,R)/U(1)
Kazama-Suzuki coset model at level k=1 have direct c=1 non-critical string
theory interpretations. After subtracting the leading singularity to procure
the 1PI effective action, we obtain the agreement with the proposal.Comment: 15 pages, v2: reference added, v3: published versio
A PKB-SPEG signaling nexus links insulin resistance with diabetic cardiomyopathy by regulating calcium homeostasis
An Infinite-Dimensional Family of Black-Hole Microstate Geometries
We construct the first explicit, smooth, horizonless black-hole microstate
geometry whose moduli space is described by an arbitrary function of one
variable and is thus infinite-dimensional. This is achieved by constructing the
scalar Green function on a simple D6 anti-D6 background, and using this Green
function to obtain the fully back-reacted solution for a supertube with varying
charge density in this background. We show that this supertube can store
parametrically more entropy than in flat space, confirming the entropy
enhancement mechanism that was predicted using brane probes. We also show that
all the local properties of the fully back-reacted solution can, in fact, be
obtained using the DBI action of an appropriate brane probe. In particular, the
supergravity and the DBI analysis yield identical functional bubble equations
that govern the relative locations of the centers. This indicates that there is
a non-renormalization theorem that protects these functional equations as one
moves in moduli space. Our construction creates configurations that are beyond
the scope of recent arguments that appear to put strong limits on the entropy
that can be found in smooth supergravity solutions.Comment: 46 pages, 1 figure, LaTe
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