Publication

Myopathy associated BAG3 mutations lead to protein aggregation by stalling Hsp70 networks

Meister-Broekema, M., Freilich, R., Jagadeesan, C., Rauch, J. N., Bengoechea, R., Motley, W. W., Kuiper, E. F. E., Minoia, M., Furtado, G. V., van Waarde, M. A. W. H., Bird, S. J., Rebelo, A., Zuchner, S., Pytel, P., Scherer, S. S., Morelli, F. F., Carra, S., Weihl, C. C., Bergink, S., Gestwicki, J. E. & Kampinga, H. H., 17-Dec-2018, In : Nature Communications. 9, 1, 14 p., 5342.

Research output: Contribution to journalArticleAcademicpeer-review

APA

Meister-Broekema, M., Freilich, R., Jagadeesan, C., Rauch, J. N., Bengoechea, R., Motley, W. W., Kuiper, E. F. E., Minoia, M., Furtado, G. V., van Waarde, M. A. W. H., Bird, S. J., Rebelo, A., Zuchner, S., Pytel, P., Scherer, S. S., Morelli, F. F., Carra, S., Weihl, C. C., Bergink, S., ... Kampinga, H. H. (2018). Myopathy associated BAG3 mutations lead to protein aggregation by stalling Hsp70 networks. Nature Communications, 9(1), [5342]. https://doi.org/10.1038/s41467-018-07718-5

Author

Meister-Broekema, Melanie ; Freilich, Rebecca ; Jagadeesan, Chandhuru ; Rauch, Jennifer N. ; Bengoechea, Rocio ; Motley, William W. ; Kuiper, E. F. Elsiena ; Minoia, Melania ; Furtado, Gabriel V. ; van Waarde, Maria A. W. H. ; Bird, Shawn J. ; Rebelo, Adriana ; Zuchner, Stephan ; Pytel, Peter ; Scherer, Steven S. ; Morelli, Federica F. ; Carra, Serena ; Weihl, Conrad C. ; Bergink, Steven ; Gestwicki, Jason E. ; Kampinga, Harm H. / Myopathy associated BAG3 mutations lead to protein aggregation by stalling Hsp70 networks. In: Nature Communications. 2018 ; Vol. 9, No. 1.

Harvard

Meister-Broekema, M, Freilich, R, Jagadeesan, C, Rauch, JN, Bengoechea, R, Motley, WW, Kuiper, EFE, Minoia, M, Furtado, GV, van Waarde, MAWH, Bird, SJ, Rebelo, A, Zuchner, S, Pytel, P, Scherer, SS, Morelli, FF, Carra, S, Weihl, CC, Bergink, S, Gestwicki, JE & Kampinga, HH 2018, 'Myopathy associated BAG3 mutations lead to protein aggregation by stalling Hsp70 networks', Nature Communications, vol. 9, no. 1, 5342. https://doi.org/10.1038/s41467-018-07718-5

Standard

Myopathy associated BAG3 mutations lead to protein aggregation by stalling Hsp70 networks. / Meister-Broekema, Melanie; Freilich, Rebecca; Jagadeesan, Chandhuru; Rauch, Jennifer N.; Bengoechea, Rocio; Motley, William W.; Kuiper, E. F. Elsiena; Minoia, Melania; Furtado, Gabriel V.; van Waarde, Maria A. W. H.; Bird, Shawn J.; Rebelo, Adriana; Zuchner, Stephan; Pytel, Peter; Scherer, Steven S.; Morelli, Federica F.; Carra, Serena; Weihl, Conrad C.; Bergink, Steven; Gestwicki, Jason E.; Kampinga, Harm H.

In: Nature Communications, Vol. 9, No. 1, 5342, 17.12.2018.

Research output: Contribution to journalArticleAcademicpeer-review

Vancouver

Meister-Broekema M, Freilich R, Jagadeesan C, Rauch JN, Bengoechea R, Motley WW et al. Myopathy associated BAG3 mutations lead to protein aggregation by stalling Hsp70 networks. Nature Communications. 2018 Dec 17;9(1). 5342. https://doi.org/10.1038/s41467-018-07718-5


BibTeX

@article{8d4d9d73e08c4ae29ea9a2b5d0b98678,
title = "Myopathy associated BAG3 mutations lead to protein aggregation by stalling Hsp70 networks",
abstract = "BAG3 is a multi-domain hub that connects two classes of chaperones, small heat shock proteins (sHSPs) via two isoleucine-proline-valine (IPV) motifs and Hsp70 via a BAG domain. Mutations in either the IPV or BAG domain of BAG3 cause a dominant form of myopathy, characterized by protein aggregation in both skeletal and cardiac muscle tissues. Surprisingly, for both disease mutants, impaired chaperone binding is not sufficient to explain disease phenotypes. Recombinant mutants are correctly folded, show unaffected Hsp70 binding but are impaired in stimulating Hsp70-dependent client processing. As a consequence, the mutant BAG3 proteins become the node for a dominant gain of function causing aggregation of itself, Hsp70, Hsp70 clients and tiered interactors within the BAG3 interactome. Importantly, genetic and pharmaceutical interference with Hsp70 binding completely reverses stress-induced protein aggregation for both BAG3 mutations. Thus, the gain of function effects of BAG3 mutants act as Achilles heel of the HSP70 machinery.",
keywords = "HEAT-SHOCK PROTEINS, CHAPERONE ACTIVITY, HEAT-SHOCK-PROTEIN-70 HSP70, QUALITY-CONTROL, DNA-DAMAGE, IN-VIVO, INTEGRITY, HSPB8, ONSET, MODULATION",
author = "Melanie Meister-Broekema and Rebecca Freilich and Chandhuru Jagadeesan and Rauch, {Jennifer N.} and Rocio Bengoechea and Motley, {William W.} and Kuiper, {E. F. Elsiena} and Melania Minoia and Furtado, {Gabriel V.} and {van Waarde}, {Maria A. W. H.} and Bird, {Shawn J.} and Adriana Rebelo and Stephan Zuchner and Peter Pytel and Scherer, {Steven S.} and Morelli, {Federica F.} and Serena Carra and Weihl, {Conrad C.} and Steven Bergink and Gestwicki, {Jason E.} and Kampinga, {Harm H.}",
year = "2018",
month = dec,
day = "17",
doi = "10.1038/s41467-018-07718-5",
language = "English",
volume = "9",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",

}

RIS

TY - JOUR

T1 - Myopathy associated BAG3 mutations lead to protein aggregation by stalling Hsp70 networks

AU - Meister-Broekema, Melanie

AU - Freilich, Rebecca

AU - Jagadeesan, Chandhuru

AU - Rauch, Jennifer N.

AU - Bengoechea, Rocio

AU - Motley, William W.

AU - Kuiper, E. F. Elsiena

AU - Minoia, Melania

AU - Furtado, Gabriel V.

AU - van Waarde, Maria A. W. H.

AU - Bird, Shawn J.

AU - Rebelo, Adriana

AU - Zuchner, Stephan

AU - Pytel, Peter

AU - Scherer, Steven S.

AU - Morelli, Federica F.

AU - Carra, Serena

AU - Weihl, Conrad C.

AU - Bergink, Steven

AU - Gestwicki, Jason E.

AU - Kampinga, Harm H.

PY - 2018/12/17

Y1 - 2018/12/17

N2 - BAG3 is a multi-domain hub that connects two classes of chaperones, small heat shock proteins (sHSPs) via two isoleucine-proline-valine (IPV) motifs and Hsp70 via a BAG domain. Mutations in either the IPV or BAG domain of BAG3 cause a dominant form of myopathy, characterized by protein aggregation in both skeletal and cardiac muscle tissues. Surprisingly, for both disease mutants, impaired chaperone binding is not sufficient to explain disease phenotypes. Recombinant mutants are correctly folded, show unaffected Hsp70 binding but are impaired in stimulating Hsp70-dependent client processing. As a consequence, the mutant BAG3 proteins become the node for a dominant gain of function causing aggregation of itself, Hsp70, Hsp70 clients and tiered interactors within the BAG3 interactome. Importantly, genetic and pharmaceutical interference with Hsp70 binding completely reverses stress-induced protein aggregation for both BAG3 mutations. Thus, the gain of function effects of BAG3 mutants act as Achilles heel of the HSP70 machinery.

AB - BAG3 is a multi-domain hub that connects two classes of chaperones, small heat shock proteins (sHSPs) via two isoleucine-proline-valine (IPV) motifs and Hsp70 via a BAG domain. Mutations in either the IPV or BAG domain of BAG3 cause a dominant form of myopathy, characterized by protein aggregation in both skeletal and cardiac muscle tissues. Surprisingly, for both disease mutants, impaired chaperone binding is not sufficient to explain disease phenotypes. Recombinant mutants are correctly folded, show unaffected Hsp70 binding but are impaired in stimulating Hsp70-dependent client processing. As a consequence, the mutant BAG3 proteins become the node for a dominant gain of function causing aggregation of itself, Hsp70, Hsp70 clients and tiered interactors within the BAG3 interactome. Importantly, genetic and pharmaceutical interference with Hsp70 binding completely reverses stress-induced protein aggregation for both BAG3 mutations. Thus, the gain of function effects of BAG3 mutants act as Achilles heel of the HSP70 machinery.

KW - HEAT-SHOCK PROTEINS

KW - CHAPERONE ACTIVITY

KW - HEAT-SHOCK-PROTEIN-70 HSP70

KW - QUALITY-CONTROL

KW - DNA-DAMAGE

KW - IN-VIVO

KW - INTEGRITY

KW - HSPB8

KW - ONSET

KW - MODULATION

U2 - 10.1038/s41467-018-07718-5

DO - 10.1038/s41467-018-07718-5

M3 - Article

C2 - 30559338

VL - 9

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 5342

ER -

ID: 73634932