ArticleJournal of molecular biology2021
Molecular Characterisation of Titin N2A and Its Binding of CARP Reveals a Titin/Actin Cross-linking Mechanism.
Article in Journal of molecular biology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 39 citations in OpenAlex.
- The titin N2A-MARP signalosome constrains muscle longitudinal hypertrophy in response to stretch.eLife · 2026Article
- Right Heart Diastology, Where Are We Now?Circulation research · 2026Review
- Integrative Multi-omics Analysis of the Human Skeletal Muscle Response to Endurance or Resistance Exercise: Findings from the Molecular Transducers of Physical Activity Consortium (MoTrPAC).bioRxiv : the preprint server for biology · 2026Article
- Mending the Achilles heels of titin in cardiac and musculoskeletal disease.Biophysical reviews · 2026Review
- Mechanically knocking out titin reveals protein tension loss as a trigger of muscle disease.Nature biomedical engineering · 2025Article
- GSK3β-driven phosphorylation of ABLIM1 regulates its interactions with titin cardiac muscle.The Journal of general physiology · 2025Article
- Titin's Intrinsically Disordered PEVK Domain Modulates Actin Polymerization.International journal of molecular sciences · 2025Article
- The calcium-binding protein S100A1 binds to titin's N2A insertion sequence in a pH-dependent manner.The Journal of general physiology · 2025Article
- ANKRD1 expression is aberrantly upregulated in the mdm mouse model of muscular dystrophy and induced by stretch through NFκB.Journal of muscle research and cell motility · 2024Article
- Research progress of ankyrin repeat domain 1 protein: an updated review.Cellular & molecular biology letters · 2024Review
- Structural domain in the Titin N2B-us region binds to FHL2 in a force-activation dependent manner.Nature communications · 2024Article
- hsa-miR-548v controls the viscoelastic properties of human cardiomyocytes and improves their relaxation rates.JCI insight · 2024Article
- Titin activates myosin filaments in skeletal muscle by switching from an extensible spring to a mechanical rectifier.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Myofilament-associated proteins with intrinsic disorder (MAPIDs) and their resolution by computational modeling.Quarterly reviews of biophysics · 2023Review
- Genetic Ablation ofBiomolecules · 2022Article
- Titin force in muscle cells alters lattice order, thick and thin filament protein formation.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Fast stretching of skeletal muscle fibres abolishes residual force enhancement.The Journal of experimental biology · 2022Article
- Understanding the molecular basis of cardiomyopathy.American journal of physiology. Heart and circulatory physiology · 2022Review
- Pairwise sequence similarity mapping with PaSiMap: Reclassification of immunoglobulin domains from titin as case study.Computational and structural biotechnology journal · 2022Article
- Protein Unfolding: Denaturant vs. Force.Biomedicines · 2021Article
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Authors and funding
15 authors at 5 institutions in 4 countries.
Funding
Abstract
Striated muscle responds to mechanical overload by rapidly up-regulating the expression of the cardiac ankyrin repeat protein, CARP, which then targets the sarcomere by binding to titin N2A in the I-band region. To date, the role of this interaction in the stress response of muscle remains poorly understood. Here, we characterise the molecular structure of the CARP-receptor site in titin (UN2A) and its binding of CARP. We find that titin UN2A contains a central three-helix bundle fold (ca 45 residues in length) that is joined to N- and C-terminal flanking immunoglobulin domains by long, flexible linkers with partial helical content. CARP binds titin by engaging an α-hairpin in the three-helix fold of UN2A, the C-terminal linker sequence, and the BC loop in Ig81, which jointly form a broad binding interface. Mutagenesis showed that the CARP/N2A association withstands sequence variations in titin N2A and we use this information to evaluate 85 human single nucleotide variants. In addition, actin co-sedimentation, co-transfection in C2C12 cells, proteomics on heart lysates, and the mechanical response of CARP-soaked myofibrils imply that CARP induces the cross-linking of titin and actin myofilaments, thereby increasing myofibril stiffness. We conclude that CARP acts as a regulator of force output in the sarcomere that preserves muscle mechanical performance upon overload stress.
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