Molecular basis of F-actin regulation and sarcomere assembly via myotilin.
Actin Cytoskeleton
/ chemistry
Actins
/ chemistry
Animals
Cells, Cultured
Cytoskeletal Proteins
/ genetics
Cytoskeleton
/ metabolism
Humans
Mice
Microfilament Proteins
/ chemistry
Muscle Contraction
/ genetics
Muscle, Skeletal
/ metabolism
Protein Binding
/ genetics
Protein Interaction Domains and Motifs
/ genetics
Protein Multimerization
/ genetics
Sarcomeres
/ genetics
Tropomyosin
/ chemistry
Journal
PLoS biology
ISSN: 1545-7885
Titre abrégé: PLoS Biol
Pays: United States
ID NLM: 101183755
Informations de publication
Date de publication:
04 2021
04 2021
Historique:
received:
29
10
2020
accepted:
16
02
2021
revised:
22
04
2021
pubmed:
13
4
2021
medline:
25
8
2021
entrez:
12
4
2021
Statut:
epublish
Résumé
Sarcomeres, the basic contractile units of striated muscle cells, contain arrays of thin (actin) and thick (myosin) filaments that slide past each other during contraction. The Ig-like domain-containing protein myotilin provides structural integrity to Z-discs-the boundaries between adjacent sarcomeres. Myotilin binds to Z-disc components, including F-actin and α-actinin-2, but the molecular mechanism of binding and implications of these interactions on Z-disc integrity are still elusive. To illuminate them, we used a combination of small-angle X-ray scattering, cross-linking mass spectrometry, and biochemical and molecular biophysics approaches. We discovered that myotilin displays conformational ensembles in solution. We generated a structural model of the F-actin:myotilin complex that revealed how myotilin interacts with and stabilizes F-actin via its Ig-like domains and flanking regions. Mutant myotilin designed with impaired F-actin binding showed increased dynamics in cells. Structural analyses and competition assays uncovered that myotilin displaces tropomyosin from F-actin. Our findings suggest a novel role of myotilin as a co-organizer of Z-disc assembly and advance our mechanistic understanding of myotilin's structural role in Z-discs.
Identifiants
pubmed: 33844684
doi: 10.1371/journal.pbio.3001148
pii: PBIOLOGY-D-20-03207
pmc: PMC8062120
doi:
Substances chimiques
Actins
0
Cytoskeletal Proteins
0
Microfilament Proteins
0
Myot protein, mouse
0
Tropomyosin
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e3001148Subventions
Organisme : Wellcome Trust
ID : 201543/Z/16
Pays : United Kingdom
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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