KBTBD13 is an actin-binding protein that modulates muscle kinetics.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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de Winter Josine M, Molenaar Joery P, Yuen Michaela, van der Pijl Robbert, Shen Shengyi, Conijn Stefan, van de Locht Martijn, Willigenburg Menne, Bogaards Sylvia Jp, van Kleef Esmee Sb, Lassche Saskia, Persson Malin, Rassier Dilson E, Sztal Tamar E, Ruparelia Avnika A, Oorschot Viola, Ramm Georg, Hall Thomas E, Xiong Zherui, Johnson Christopher N, Li Frank, Kiss Balazs, Lozano-Vidal Noelia, Boon Reinier A, Marabita Manuela, Nogara Leonardo, Blaauw Bert, Rodenburg Richard J, Küsters Benno, Doorduin Jonne, Beggs Alan H, Granzier Henk, Campbell Ken, Ma Weikang, Irving Thomas, Malfatti Edoardo, Romero Norma B, Bryson-Richardson Robert J, van Engelen Baziel Gm, Voermans Nicol C, Ottenheijm Coen Ac
Аннотация
The 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 Kbtbd13R408C-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.