title: Chaperone activity of small heat shock proteins underlies therapeutic efficacy in experimental autoimmune encephalomyelitis.
abstract: To determine whether the therapeutic activity of αB crystallin, small heat shock protein B5 (HspB5), was shared with other human sHsps, a set of seven human family members, a mutant of HspB5 G120 known to exhibit reduced chaperone activity, and a mycobacterial sHsp were expressed and purified from bacteria. Each of the recombinant proteins was shown to be a functional chaperone, capable of inhibiting aggregation of denatured insulin with varying efficiency. When injected into mice at the peak of disease, they were all effective in reducing the paralysis in experimental autoimmune encephalomyelitis. Additional structure activity correlations between chaperone activity and therapeutic function were established when linear regions within HspB5 were examined. A single region, corresponding to residues 73-92 of HspB5, forms amyloid fibrils, exhibited chaperone activity, and was an effective therapeutic for encephalomyelitis. The linkage of the three activities was further established by demonstrating individual substitutions of critical hydrophobic amino acids in the peptide resulted in the loss of all of the functions.
authors.affiliation: Department Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305-5316, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Kurnellas
authors.forename: Sara E
authors.initials: SE
authors.lastname: Brownell
authors.forename: Leon
authors.initials: L
authors.lastname: Su
authors.forename: Andrey V
authors.initials: AV
authors.lastname: Malkovskiy
authors.forename: Jayakumar
authors.initials: J
authors.lastname: Rajadas
authors.forename: Gregory
authors.initials: G
authors.lastname: Dolganov
authors.forename: Sidharth
authors.initials: S
authors.lastname: Chopra
authors.forename: Gary K
authors.initials: GK
authors.lastname: Schoolnik
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Sobel
authors.forename: Jonathan
authors.initials: J
authors.lastname: Webster
authors.forename: Shalina S
authors.initials: SS
authors.lastname: Ousman
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Becker
authors.forename: Lawrence
authors.initials: L
authors.lastname: Steinman
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Rothbard
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D051379:Mice; D020125:Mutation, Missense; D010243:Paralysis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D038203:alpha-Crystallin B Chain / Q000235:genetics / Q000494:pharmacology*
chemical_list: C059215:CRYAB protein, human; D038203:alpha-Crystallin B Chain