RT Journal Article
SR Electronic
T1 Dysregulation of HSP27 oligomerization and interactions by a neuropathy-causing mutation in the IPV motif
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 708180
DO 10.1101/708180
A1 T. Reid Alderson
A1 Elias Adriaenssens
A1 Bob Asselbergh
A1 Iva Pritišanac
A1 Heidi Y. Gastall
A1 Marielle Wälti
A1 John M. Louis
A1 Vincent Timmerman
A1 Andrew J. Baldwin
A1 Justin L. P. Benesch
YR 2019
UL http://biorxiv.org/content/early/2019/07/19/708180.abstract
AB HSP27 (HSPB1) is a systemically expressed human small heat-shock protein that forms large, dynamic oligomers and functions in various aspects of cellular homeostasis. Mutations in HSP27 cause Charcot-Marie-Tooth disease, the most commonly inherited disorder of the peripheral nervous system. A particularly severe form of the disease is triggered by the P182L mutation within the conserved C-terminal IPV motif of HSP27, also known as the IxI/V motif. Here, we observed that the P182L variant of HSP27 lost its ability to prevent the aggregation of client proteins and formed significantly larger oligomers both in vitro and in vivo. NMR spectroscopy revealed that P182L binds its α-crystallin domain with a significantly lower affinity and association rate, thus rendering the binding site more available for other interactors. We identified 22 IxI/V-containing proteins that are known to interact with HSP27 and could therefore bind with enhanced affinity to the P182L variant. Co-immunoprecipitation experiments indicate that the co-chaperone BAG3, which contains two IPV motifs, indeed binds with higher affinity to the P182L variant of HSP27. Our results demonstrate that disruption of the HSP27 IxI/V binding process dysregulates its oligomerization and downstream protein-protein interactions.