TY - JOUR
T1 - Chaperone activity of small heat shock proteins underlies therapeutic efficacy in experimental autoimmune encephalomyelitis
AU - Kurnellas, Michael P.
AU - Brownell, Sara E.
AU - Su, Leon
AU - Malkovskiy, Andrey V.
AU - Rajadas, Jayakumar
AU - Dolganov, Gregory
AU - Chopra, Sidharth
AU - Schoolnik, Gary K.
AU - Sobel, Raymond A.
AU - Webster, Jonathan
AU - Ousman, Shalina S.
AU - Becker, Rachel A.
AU - Steinman, Lawrence
AU - Rothbard, Jonathan B.
PY - 2012/10/19
Y1 - 2012/10/19
N2 - 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.Asingle 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.
AB - 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.Asingle 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.
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U2 - 10.1074/jbc.M112.371229
DO - 10.1074/jbc.M112.371229
M3 - Article
C2 - 22955287
AN - SCOPUS:84867808822
SN - 0021-9258
VL - 287
SP - 36423
EP - 36434
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 43
ER -