Molecular mechanisms underlying polyalanine diseases

Messaed, Christiane; Rouleau, Guy

doi:10.1016/j.nbd.2009.02.013

Cited by 77 publications

(90 citation statements)

References 91 publications

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“…53 Although, the disease mechanisms are uncertain, it is suggested that the polyalanine tracts lead to aberrant protein-protein interactions. 54 Using polyalanine peptides as a model system, thus provides a method to understand sequence-independent membrane effects as well as their possible role in healthy and diseased conditions.…”

Section: Introductionmentioning

confidence: 99%

Thermodynamic and kinetic characterization of transmembrane helix association

Pawar

Deshpande

Gopal

et al. 2015

Phys. Chem. Chem. Phys.

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The transient dimerization of transmembrane proteins is an important event in several cellular processes and computational methods are being increasingly used to quantify their underlying energetics. Here, we probe the thermodynamics and kinetics of a simple transmembrane dimer to understand membrane protein association. A multi-step framework has been developed in which the dimerization profiles are calculated from coarse-grain molecular dynamics simulations, followed by meso-scale simulations using parameters calculated from the coarse-grain model. The calculated value of DG assoc is approx. À20 kJ mol À1 and is consistent between three methods. Interestingly, the meso-scale stochastic model reveals low dimer percentages at physiologically-relevant concentrations, despite a favorable DG assoc . We identify generic driving forces arising from the protein backbone and lipid bilayer and complementary factors, such as protein density, that govern self-interactions in membranes. Our results provide an important contribution in understanding membrane protein organization and linking molecular, nano-scale computational studies to meso-scale experimental data.

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Section: Introductionmentioning

confidence: 99%

Thermodynamic and kinetic characterization of transmembrane helix association

Pawar

Deshpande

Gopal

et al. 2015

Phys. Chem. Chem. Phys.

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“…[24,25] The disease etiology is suggested to arise from the formation of b sheets that aggregate into well-ordered fibrils, [26] although the exact mechanism of cellular toxicity is not clear. [25] It has been suggested that the fibrils consist of antiparallel sheets, [27] in common with the fibrils that are found in polyglutamine expansion diseases. [28,29] Therefore, the structures described in this study may be useful in modeling polyA expansion fibrils.…”

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confidence: 99%

Two Different Packing Arrangements of Antiparallel Polyalanine

et al. 2011

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“…Another neuromuscular disorder that arises from a microsatellite expansion in the coding region of an RNA-binding protein is oculopharyngeal muscular dystrophy (OPMD) (Brais, 2009; Messaed & Rouleau, 2009). OPMD is a late-onset muscular dystrophy characterized by muscle weakness, ptosis (eyelid drooping) and dysphagia (difficulty in swallowing that may lead to aspiration pneumonia).…”

Section: 5 An Intrinsic Curse: Microsatellite Expansions In Rna-binmentioning

confidence: 99%

RNA-Binding Protein Misregulation in Microsatellite Expansion Disorders

Goodwin

Swanson

2014

Advances in Experimental Medicine and Biology

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RNA-binding proteins (RBPs) play pivotal roles in multiple cellular pathways from transcription to RNA turnover by interacting with RNA sequence and/or structural elements to form distinct RNA-protein complexes. Since these complexes are required for the normal regulation of gene expression, mutations that alter RBP functions may result in a cascade of deleterious events that lead to severe disease. Here, we focus on a group of hereditary disorders, the microsatellite expansion diseases, which alter RBP activities and result in abnormal neurological and neuromuscular phenotypes. While many of these diseases are classified as adult-onset disorders, mounting evidence indicates that disruption of normal RNA-protein interaction networks during embryogenesis modifies developmental pathways which ultimately leads to disease manifestations later in life. Efforts to understand the molecular basis of these disorders has already uncovered novel pathogenic mechanisms, including RNA toxicity and repeat-associated non-ATG (RAN) translation, and current studies suggest that additional surprising insights into cellular regulatory pathways will emerge in the future.

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Molecular mechanisms underlying polyalanine diseases

Cited by 77 publications

References 91 publications

Thermodynamic and kinetic characterization of transmembrane helix association

Thermodynamic and kinetic characterization of transmembrane helix association

Two Different Packing Arrangements of Antiparallel Polyalanine

RNA-Binding Protein Misregulation in Microsatellite Expansion Disorders

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