The excised ACD of both αB-crystallin and HSP27 can display potent chaperone activity in vitro 35, 39 suggesting that important aspects of sHSP function are encoded within this domain. Based on evidence from the closely related human sHSP paralog, αB-crystallin (HSPB5) 38, the ACD is likely structurally similar in the context of the full-length oligomeric protein and in its isolated dimeric form. Under oxidising conditions, the dimer interface in HSP27 is reinforced by an intermolecular disulphide bond involving C137 from adjacent subunits centred on a two-fold axis 34, 35, 36. The subunits in the dimer adopt an immunoglobulin-like fold, and assemble through the formation of an extended β-sheet upon pairwise association of their β6 + 7 strands 34, 35, 36, 37. Removal of the C-terminal region (CTR) and N-terminal domain (NTD) leaves a conserved ~80-residue, α-crystallin domain (ACD) that does not assemble beyond a dimer (Fig. Obtaining high-resolution structural information on HSP27 is challenging, as it assembles into a polydisperse ensemble of inter-converting oligomers ranging from approximately 12 to 36 subunits 31, 32, 33 of average molecular mass of ca. Intriguingly, variants of HSP27 that have an increased tendency to form free monomers display hyperactivity both in vitro and in vivo 29, 30.Īlthough functionally relevant, no sHSP monomer has yet been characterised at atomic resolution, as they are typically present at low abundance in equilibrium with higher-order oligomers. The chaperone activities of many sHSPs have been characterised in vitro 23, but the active sHSP species remains unclear, with large oligomers 24, 25, small oligomers 26, 27, and dimers 28 all implicated. Like other mammalian sHSPs, HSP27 assembles to form a wide range of oligomers 20 whose constituent monomers and dimers freely exchange between oligomers 21, 22. Accordingly, the presence of this disulphide bond impacts on the activity of HSP27 in vitro 15, 16, 17 and on the resistance of cells to oxidative stress 13, 14, 18, 19. This cysteine is highly conserved in HSP27 orthologs but not found in other mammalian sHSPs 14, implying that it plays an important functional role. HSP27 is directly sensitive to the intracellular redox state via its lone cysteine residue (C137), which controls dimerisation by forming an intermolecular disulphide bond in vivo even under the reducing conditions of the cytosol 13. These maladies are themselves linked to oxidative stress 9, 10, and recent studies have indicated that the reducing environment of the cytosol progressively transitions to an oxidising environment over the lifetime of an organism 11, 12. Numerous mutations in HSP27 have been linked to different neuropathies, including distal hereditary motor neuropathy (dHMN) and Charcot–Marie–Tooth (CMT) disease 7, 8, the most commonly inherited neuromuscular disorder. The most abundant sHSP in humans 2, HSP27 (or HSPB1), is systemically expressed under basal conditions and upregulated by oxidative stress 3, during aging 4, and in cancers 5 and protein deposition diseases 6. Įric Kohn of Indiewire graded the film a C−, saying that it had flat direction and a mediocre script and said "As a vehicle for WWE champ Paul "Triple H" Levesque, it's haplessly stuck on cruise control." Nick Schager of Slant Magazine gave it half-a-star out of four, criticizing the script, direction and characters saying that "this hulk-with-a-heart-of-gold fable embraces banalities with a vigor matched only by its lack of imagination.Small heat-shock proteins (sHSPs) are a class of molecular chaperones present in all kingdoms of life and exhibit diverse functionality, from modulating protein aggregation to maintaining cytoskeletal integrity and regulating apoptosis 1. Metacritic gives a score of 33/100 based on reviews from 11 critics. Review aggregation website Rotten Tomatoes gives the film a score of 29% based on 17 reviews, with an average rating of 3.7/10. The Chaperone met with negative reviews from critics. WWE announced that filming in New Orleans started in June 2010. Kevin Corrigan as Phillip "The Cat" Larue.Paul "Triple H" Levesque as Raymond "Ray" Bradstone.The robbery is a disaster and now Ray must deal with an enraged Larue while driving a school bus full of kids. Ray changes his mind at the last second, choosing to chaperone a field trip with Sally's class and leaving the thieves without a worthy means of escape. As Ray struggles to find honest work, he agrees to take one last job with his old bank-robbing crew, led by Phillip Larue. Ray Bradstone, a talented getaway driver, is determined to go straight, be a better parent to his daughter Sally, and make amends with his ex-wife, Lynne. It stars Triple H, Yeardley Smith, Ariel Winter, Kevin Corrigan, José Zúñiga, Kevin Rankin, Enrico Colantoni, and Israel Broussard. The Chaperone is a 2011 American crime comedy film directed by Stephen Herek, and also produced by WWE Studios.
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