Cofilin-2 controls actin filament length in muscle sarcomeres.
ADF/cofilins drive cytoskeletal dynamics by promoting the disassembly of "aged" ADP-actin filaments. Mammals express several ADF/cofilin isoforms, but their specific biochemical activities and cellular functions have not been studied in detail. Here, we demonstrate that the muscle-specific isoform cofilin-2 promotes actin filament disassembly in sarcomeres to control the precise length of thin filaments in the contractile apparatus. In contrast to other isoforms, cofilin-2 efficiently binds and disassembles both ADP- and ATP/ADP-Pi-actin filaments. We mapped surface-exposed cofilin-2-specific residues required for ATP-actin binding and propose that these residues function as an "actin nucleotide-state sensor" among ADF/cofilins. The results suggest that cofilin-2 evolved specific biochemical and cellular properties that allow it to control actin dynamics in sarcomeres, where filament pointed ends may contain a mixture of ADP- and ATP/ADP-Pi-actin subunits. Our findings also offer a rationale for why cofilin-2 mutations in humans lead to myopathies.
Institute of Biotechnology, University of Helsinki, P.O. Box 56, 00014 Helsinki, Finland.
Elena
E
Kremneva
Institute of Biotechnology, University of Helsinki, P.O. Box 56, 00014 Helsinki, Finland.
Maarit H
MH
Makkonen
Institute of Biotechnology, University of Helsinki, P.O. Box 56, 00014 Helsinki, Finland.
Aneta
A
Skwarek-Maruszewska
Institute of Biotechnology, University of Helsinki, P.O. Box 56, 00014 Helsinki, Finland.
Gergana
G
Gateva
Laboratoire de Physiologie Cellulaire et Végétale, Institut de Recherches en Technologies et Sciences pour le Vivant, iRTSV, CNRS/CEA/INRA/UJF, 38054 Grenoble, France.
Alphee
A
Michelot
Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Roberto
R
Dominguez
Institute of Biotechnology, University of Helsinki, P.O. Box 56, 00014 Helsinki, Finland. Electronic address: pekka.lappalainen@helsinki.fi.
Pekka
P
Lappalainen
D008841:Actin Cytoskeleton / Q000378:metabolism / Q000502:physiology*; D000199:Actins / Q000378:metabolism; D000244:Adenosine Diphosphate / Q000031:analogs & derivatives / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D051338:Cofilin 1 / Q000235:genetics; D051340:Cofilin 2 / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000502:physiology*; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering; D051381:Rats; D012518:Sarcomeres / Q000502:physiology*; D016415:Sequence Alignment
C042634:ADP-G-actin; C022920:ATP-G-actin; D000199:Actins; D051338:Cofilin 1; D051340:Cofilin 2; D034741:RNA, Small Interfering; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate