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2 results on '"Allison TM"'

1. HspB1 phosphorylation regulates its intramolecular dynamics and mechanosensitive molecular chaperone interaction with filamin C

Author

Collier, MP, Alderson, TR, De Villiers, CP, Nicholls, D, Gastall, HY, Allison, TM, Degiacomi, MT, Jiang, H, Mlynek, G, Fürst, DO, Van Der Ven, PFM, Djinovic-Carugo, K, Baldwin, AJ, Watkins, H, Gehmlich, K, and Benesch, JLP

Subjects
Male, Protein Denaturation, Protein Folding, animal structures, Filamins, Biophysics, macromolecular substances, Protein Structure, Secondary, Mice, Protein Domains, Structural Biology, Animals, Humans, Phosphorylation, Heat-Shock Proteins, Research Articles, Mice, Knockout, Binding Sites, Myocardium, SciAdv r-articles, Heart, Recombinant Proteins, body regions, Mice, Inbred C57BL, Mutation, Stress, Mechanical, Molecular Chaperones, Research Article
Abstract

The molecular chaperone HspB1 regulates the biomechanical extension of the heart muscle protein filamin C upon stress., Mechanical force–induced conformational changes in proteins underpin a variety of physiological functions, typified in muscle contractile machinery. Mutations in the actin-binding protein filamin C (FLNC) are linked to musculoskeletal pathologies characterized by altered biomechanical properties and sometimes aggregates. HspB1, an abundant molecular chaperone, is prevalent in striated muscle where it is phosphorylated in response to cues including mechanical stress. We report the interaction and up-regulation of both proteins in three mouse models of biomechanical stress, with HspB1 being phosphorylated and FLNC being localized to load-bearing sites. We show how phosphorylation leads to increased exposure of the residues surrounding the HspB1 phosphosite, facilitating their binding to a compact multidomain region of FLNC proposed to have mechanosensing functions. Steered unfolding of FLNC reveals that its extension trajectory is modulated by the phosphorylated region of HspB1. This may represent a posttranslationally regulated chaperone-client protection mechanism targeting over-extension during mechanical stress.

Published
2019

2. Ligand binding to a G protein-coupled receptor captured in a mass spectrometer.

Author

Yen HY, Hopper JTS, Liko I, Allison TM, Zhu Y, Wang D, Stegmann M, Mohammed S, Wu B, and Robinson CV

Subjects
Adenosine Diphosphate chemistry, Adenosine Diphosphate metabolism, Models, Molecular, Molecular Conformation, Phosphorylation, Protein Binding, Receptors, G-Protein-Coupled metabolism, Receptors, Purinergic P2Y1 chemistry, Receptors, Purinergic P2Y1 metabolism, Structure-Activity Relationship, Ligands, Mass Spectrometry, Receptors, G-Protein-Coupled chemistry
Abstract

G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptors belong to the largest family of membrane-embedded cell surface proteins and are involved in a diverse array of physiological processes. Despite progress in the mass spectrometry of membrane protein complexes, G protein-coupled receptors have remained intractable because of their low yield and instability after extraction from cell membranes. We established conditions in the mass spectrometer that preserve noncovalent ligand binding to the human purinergic receptor P2Y 1 . Results established differing affinities for nucleotides and the drug MRS2500 and link antagonist binding with the absence of receptor phosphorylation. Overall, therefore, our results are consistent with drug binding, preventing the conformational changes that facilitate downstream signaling. More generally, we highlight opportunities for mass spectrometry to probe effects of ligand binding on G protein-coupled receptors.

Published
2017
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