KBTBD13 is an actin-binding protein that modulates muscle kinetics
Authorde Winter, Josine M
Molenaar, Joery P
van der Pijl, Robbert
van de Locht, Martijn
Bogaards, Sylvia Jp
van Kleef, Esmee Sb
Rassier, Dilson E
Sztal, Tamar E
Ruparelia, Avnika A
Hall, Thomas E
Johnson, Christopher N
Boon, Reinier A
Rodenburg, Richard J
Beggs, Alan H
Romero, Norma B
Bryson-Richardson, Robert J
van Engelen, Baziel Gm
Voermans, Nicol C
Ottenheijm, Coen Ac
AffiliationUniv Arizona, Dept Cellular & Mol Med
MetadataShow full item record
PublisherAMER SOC CLINICAL INVESTIGATION INC
Citationde Winter, J. M., Molenaar, J. P., Yuen, M., van der Pijl, R., Shen, S., Conijn, S., … Ottenheijm, C. A. C. (2020). KBTBD13 is an actin-binding protein that modulates muscle kinetics. Journal of Clinical Investigation, 130(2), 754–767. https://doi.org/10.1172/jci124000
RightsCopyright © 2020, American Society for Clinical Investigation.
Collection InformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at firstname.lastname@example.org.
AbstractThe mechanisms that modulate the kinetics of muscle relaxation are critically important for muscle function. A prime example of the impact of impaired relaxation kinetics is nemaline myopathy caused by mutations in KBTBD13 (NEM6). In addition to weakness, NEM6 patients have slow muscle relaxation, compromising contractility and daily life activities. The role of KBTBD13 in muscle is unknown, and the pathomechanism underlying NEM6 is undetermined. A combination of transcranial magnetic stimulation-induced muscle relaxation, muscle fiber- and sarcomere-contractility assays, low-angle x-ray diffraction, and superresolution microscopy revealed that the impaired muscle-relaxation kinetics in NEM6 patients are caused by structural changes in the thin filament, a sarcomeric microstructure. Using homology modeling and binding and contractility assays with recombinant KBTBD13, Kbtbd13-knockout and Kbtbd13(R)(408c)-knockin mouse models, and a GFP-labeled Kbtbd13-transgenic zebrafish model, we discovered that KBTBD13 binds to actin - a major constituent of the thin filament - and that mutations in KBTBD13 cause structural changes impairing muscle-relaxation kinetics. We propose that this actin-based impaired relaxation is central to NEM6 pathology.
VersionFinal published version
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- Authors: Campbell SG, Niederer SA
- Issue date: 2020 Feb 3
- Dysfunctional sarcomere contractility contributes to muscle weakness in ACTA1-related nemaline myopathy (NEM3).
- Authors: Joureau B, de Winter JM, Conijn S, Bogaards SJP, Kovacevic I, Kalganov A, Persson M, Lindqvist J, Stienen GJM, Irving TC, Ma W, Yuen M, Clarke NF, Rassier DE, Malfatti E, Romero NB, Beggs AH, Ottenheijm CAC
- Issue date: 2018 Feb
- Dominant mutations in KBTBD13, a member of the BTB/Kelch family, cause nemaline myopathy with cores.
- Authors: Sambuughin N, Yau KS, Olivé M, Duff RM, Bayarsaikhan M, Lu S, Gonzalez-Mera L, Sivadorai P, Nowak KJ, Ravenscroft G, Mastaglia FL, North KN, Ilkovski B, Kremer H, Lammens M, van Engelen BG, Fabian V, Lamont P, Davis MR, Laing NG, Goldfarb LG
- Issue date: 2010 Dec 10
- Deleting exon 55 from the nebulin gene induces severe muscle weakness in a mouse model for nemaline myopathy.
- Authors: Ottenheijm CA, Buck D, de Winter JM, Ferrara C, Piroddi N, Tesi C, Jasper JR, Malik FI, Meng H, Stienen GJ, Beggs AH, Labeit S, Poggesi C, Lawlor MW, Granzier H
- Issue date: 2013 Jun
- KBTBD13 interacts with Cullin 3 to form a functional ubiquitin ligase.
- Authors: Sambuughin N, Swietnicki W, Techtmann S, Matrosova V, Wallace T, Goldfarb L, Maynard E
- Issue date: 2012 May 18