156 research outputs found

    The Role of Tropomyosin in Cardiac Function and Disease

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    Phosphorylation of cardiac sarcomeric proteins plays a major role in the regulation of physiological performance of the heart. Tropomyosin, an essential thin filament protein, regulates muscle contraction and relaxation through its interactions with actin, myosin, and the troponin complex. Studies demonstrate that changes in tropomyosin phosphorylation occur both postpartum and in response to cardiac hypertrophy and heart failure. To address the significance of tropomyosin phosphorylation on cardiac function, we conducted experiments to ascertain the effects of constitutive pseudophosphorylation, dephosphorylation, and dephosphorylation in hypertrophic cardiomyopathic hearts. Recent work demonstrates that pseudophosphorylation of tropomyosin results in dilated cardiomyopathy. Tropomyosin dephosphorylation results in a compensated or physiological cardiac hypertrophic phenotype. In addition, we demonstrated that tropomyosin dephosphorylation phenotypically rescues hearts undergoing cardiac hypertrophy. In summary, these studies collectively demonstrate a significant biological and physiological role for tropomyosin phosphorylation under both normal and cardiomyopathic conditions

    Cardiomyopathy: Getting Bigger All the Time - Lessons Learned about Heart Disease from Tropomyosin

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    In 1990, John and Christine Seidman uncovered the genetic association between mutations in sarcomeric contractile proteins and hypertrophic cardiomyopathy. Since then, the increase in knowledge and understanding of this disease has increased exponentially. Although pathologies associated with the various cardiomyopathies are vastly different, in some cases, the same proteins are causative, but with different genetic mutations. The focus of this article will be on hypertrophic and dilated cardiomyopathies, which are often caused by mutations in sarcomeric contractile proteins. Tropomyosin, a thin filament protein, serves as a paradigm to illustrate how different mutations within the same protein can generate the hypertrophic or dilated cardiomyopathic condition. As such, the significant advances in information derived from basic science investigations has led to the development of novel therapeutics in the treatment of these pathological diseases. This article will illustrate linkages which occur to bridge scientific advances to clinical treatments in cardiomyopathic patients

    Peptide exchange on MHC-I by TAPBPR is driven by a negative allostery release cycle.

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    Chaperones TAPBPR and tapasin associate with class I major histocompatibility complexes (MHC-I) to promote optimization (editing) of peptide cargo. Here, we use solution NMR to investigate the mechanism of peptide exchange. We identify TAPBPR-induced conformational changes on conserved MHC-I molecular surfaces, consistent with our independently determined X-ray structure of the complex. Dynamics present in the empty MHC-I are stabilized by TAPBPR and become progressively dampened with increasing peptide occupancy. Incoming peptides are recognized according to the global stability of the final pMHC-I product and anneal in a native-like conformation to be edited by TAPBPR. Our results demonstrate an inverse relationship between MHC-I peptide occupancy and TAPBPR binding affinity, wherein the lifetime and structural features of transiently bound peptides control the regulation of a conformational switch located near the TAPBPR binding site, which triggers TAPBPR release. These results suggest a similar mechanism for the function of tapasin in the peptide-loading complex

    De novo CCND2 mutations leading to stabilization of cyclin D2 cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome

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    Activating mutations in genes encoding phosphatidylinositol 3-kinase (PI3K)-AKT pathway components cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH, OMIM 603387). Here we report that individuals with MPPH lacking upstream PI3K-AKT pathway mutations carry de novo mutations in CCND2 (encoding cyclin D2) that are clustered around a residue that can be phosphorylated by glycogen synthase kinase 3β (GSK-3β). Mutant CCND2 was resistant to proteasomal degradation in vitro compared to wild-type CCND2. The PI3K-AKT pathway modulates GSK-3β activity, and cells from individuals with PIK3CA, PIK3R2 or AKT3 mutations showed similar CCND2 accumulation. CCND2 was expressed at higher levels in brains of mouse embryos expressing activated AKT3. In utero electroporation of mutant CCND2 into embryonic mouse brains produced more proliferating transfected progenitors and a smaller fraction of progenitors exiting the cell cycle compared to cells electroporated with wild-type CCND2. These observations suggest that cyclin D2 stabilization, caused by CCND2 mutation or PI3K-AKT activation, is a unifying mechanism in PI3K-AKT–related megalencephaly syndromes

    Bentonite mechanical evolution – experimental work for the support of model development and validation

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    The objectives of the Beacon experimental studies are to provide input data and parameters for development and validation of models and to reduce uncertainties about conditions and phenomena influencing bentonite homogenisation. Both the homogenisation of an initially inhomogeneous bentonite system and the persistence or development of inhomogeneities in the bentonite system under various mechanical and hydraulic conditions are investigated. Eight experiment teams perform tests involving different bentonite materials and different hydraulic and mechanical boundary conditions. The experiments performed within Beacon address the hydro-mechanical behaviour of macroscopically homogeneous bentonite materials, (the influence of initial granulometry and of hydro-mechanical paths on the final properties of bentonite, constant load and constant volume tests on the Czech Cerny vrch bentonite), the issue of swelling into a limited void (experiments performed in constant volume cells partially filled with bentonite, at different scales and with different emphases), binary mixtures or artificial inhomogeneities (experiments using bentonite block/pellet or pellet/powder mixtures, and the influence of the degree of saturation on the shearing behaviour at a bentonite – steel interface. This report is the first Beacon WP4 deliverable on experimental work and presents the status at Beacon mid-term
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