Increased monomerization of mutant HSPB1 leads to protein hyperactivity in CMT

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J Biol Chem. 2010 Feb 23

Increased monomerization of mutant HSPB1 leads to protein hyperactivity in

Charcot-Marie-Tooth neuropathy.

Almeida-Souza L, Goethals S, de Winter V, Dierick I, Gallardo R, Van Durme J,

Irobi J, Gettemans J, Rousseau F, Schymkowitz J, Timmerman V, Janssens S.

VIB and University of Antwerp, Belgium;

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 (CMT) 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 to 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 wild-type HSPB1 protein undergoes monomerization

during heat-shock activation, strongly suggesting that the monomer is the active

form of the HSPB1 protein.