Increased Monomerization of Mutant HSPB1 Leads to Protein Hyperactivity in Charcot-Marie-Tooth Neuropathy

被引:88
作者
Almeida-Souza, Leonardo [5 ]
Goethals, Sofie [5 ]
de Winter, Vicky [5 ]
Dierick, Ines [5 ]
Gallardo, Rodrigo [2 ]
Van Durme, Joost [2 ]
Irobi, Joy [5 ]
Gettemans, Jan [3 ,4 ]
Rousseau, Frederic [2 ]
Schymkowitz, Joost [2 ]
Timmerman, Vincent [1 ,5 ]
Janssens, Sophie [5 ]
机构
[1] Univ Antwerp, Peripheral Neuropathy Grp, VIB Dept Mol Genet, CDE, B-2610 Antwerp, Belgium
[2] Vrije Univ Brussel, VIB Switch Lab, B-1050 Brussels, Belgium
[3] Univ Ghent, VIB Dept Med Prot Res, B-9000 Ghent, Belgium
[4] Univ Ghent, Dept Biochem, Fac Med & Hlth Sci, B-9000 Ghent, Belgium
[5] Inst Born Bunge, Neurogenet Lab, B-2610 Antwerp, Belgium
关键词
HEAT-SHOCK-PROTEIN; ALPHA-CRYSTALLIN DOMAIN; A-CRYSTALLIN; SUBUNIT INTERACTIONS; CHAPERONE ACTIVITY; B-CRYSTALLIN; IN-VIVO; HSP27; MUTATION; DISSOCIATION;
D O I
10.1074/jbc.M109.082644
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Small heat shock proteins are molecular chaperones capable of maintaining denatured proteins in a folding-competent state. We have previously shown that missense mutations in the small heat shock protein HSPB1 (HSP27) cause distal hereditary motor neuropathy and axonal Charcot-Marie-Tooth disease. Here we investigated the biochemical consequences of HSPB1 mutations that are known to cause peripheral neuropathy. In contrast to other chaperonopathies, our results revealed that particular HSPB1 mutations presented higher chaperone activity compared with wild type. Hyperactivation of HSPB1 was accompanied by a change from its wild-type dimeric state to a monomer without dissociation of the 24-meric state. Purification of protein complexes from wild-type and HSPB1 mutants showed that the hyperactive isoforms also presented enhanced binding to client proteins. Furthermore, we show that the wildtype HSPB1 protein undergoes monomerization during heat-shock activation, strongly suggesting that the monomer is the active form of the HSPB1 protein.
引用
收藏
页码:12778 / 12786
页数:9
相关论文
共 43 条
[1]   A mutation in the small heat-shock protein HSPB1 leading to distal hereditary motor neuronopathy disrupts neurofilament assembly and the axonal transport of specific cellular cargoes [J].
Ackerley, S ;
James, PA ;
Kalli, A ;
French, S ;
Davies, KE ;
Talbot, K .
HUMAN MOLECULAR GENETICS, 2006, 15 (02) :347-354
[2]   The R116C mutation in αA-crystallin diminishes its protective ability against stress-induced lens epithelial cell apoptosis [J].
Andley, UP ;
Patel, HC ;
Xi, JH .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (12) :10178-10186
[3]   The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling [J].
Arnold, K ;
Bordoli, L ;
Kopp, J ;
Schwede, T .
BIOINFORMATICS, 2006, 22 (02) :195-201
[4]   Crystal Structures of α-Crystallin Domain Dimers of αB-Crystallin and Hsp20 [J].
Bagneris, C. ;
Bateman, O. A. ;
Naylor, C. E. ;
Cronin, N. ;
Boelens, W. C. ;
Keep, N. H. ;
Slingsby, C. .
JOURNAL OF MOLECULAR BIOLOGY, 2009, 392 (05) :1242-1252
[5]   Charcot-marie-tooth disease:: A clinico-genetic confrontation [J].
Barisic, N. ;
Claeys, K. G. ;
Sirotkovic-Skerlev, M. ;
Lofgren, A. ;
Nelis, E. ;
De Jonghe, P. ;
Timmerman, V. .
ANNALS OF HUMAN GENETICS, 2008, 72 :416-441
[6]   Small heat shock protein activity is regulated by variable oligomeric substructure [J].
Benesch, Justin L. P. ;
Ayoub, Marina ;
Robinson, Carol V. ;
Aquilina, J. Andrew .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2008, 283 (42) :28513-28517
[7]   CONTROLLING THE FALSE DISCOVERY RATE - A PRACTICAL AND POWERFUL APPROACH TO MULTIPLE TESTING [J].
BENJAMINI, Y ;
HOCHBERG, Y .
JOURNAL OF THE ROYAL STATISTICAL SOCIETY SERIES B-STATISTICAL METHODOLOGY, 1995, 57 (01) :289-300
[8]   Site-directed spin labeling study of subunit interactions in the α-crystallin domain of small heat-shock proteins -: Comparison of the oligomer symmetry in αA-crystallin, HSP 27, and HSP 16.3 [J].
Berengian, AR ;
Parfenova, M ;
Mchaourab, HS .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (10) :6305-6314
[9]  
Borrelli MJ, 2002, CELL STRESS CHAPERON, V7, P281, DOI 10.1379/1466-1268(2002)007<0281:SPBAFH>2.0.CO
[10]  
2