Leiomodin creates a leaky cap at the pointed end of actin-thin filaments
Improper lengths of actin-thin filaments are associated with altered contractile activity and lethal myopathies. Leiomodin, a member of the tropomodulin family of proteins, is critical in thin filament assembly and maintenance; however, its role is under dispute. Using nuclear magnetic resonance data and molecular dynamics simulations, we generated the first atomic structural model of the binding interface between the tropomyosin-binding site of cardiac leiomodin and the N-terminus of striated muscle tropomyosin. Our structural data indicate that the leiomodin/tropomyosin complex only forms at the pointed end of thin filaments, where the tropomyosin N-terminus is not blocked by an adjacent tropomyosin protomer. This discovery provides evidence supporting the debated mechanism where leiomodin and tropomodulin regulate thin filament lengths by competing for thin filament binding. Data from experiments performed in cardiomyocytes provide additional support for the competition model; specifically, expression of a leiomodin mutant that is unable to interact with tropomyosin fails to displace tropomodulin at thin filament pointed ends and fails to elongate thin filaments. Together with previous structural and biochemical data, we now propose a molecular mechanism of actin polymerization at the pointed end in the presence of bound leiomodin. In the proposed model, the N-terminal actin-binding site of leiomodin can act as a "swinging gate" allowing limited actin polymerization, thus making leiomodin a leaky pointed-end cap. Results presented in this work answer long-standing questions about the role of leiomodin in thin filament length regulation and maintenance.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2020 |
|---|---|
| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:18 |
|---|---|
| Enthalten in: |
PLoS biology - 18(2020), 9 vom: 08. Sept., Seite e3000848 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Tolkatchev, Dmitri [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 20.10.2020 Date Revised 14.12.2021 published: Electronic-eCollection Citation Status MEDLINE |
|---|
| doi: |
10.1371/journal.pbio.3000848 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM314707921 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM314707921 | ||
| 003 | DE-627 | ||
| 005 | 20231225153320.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2020 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1371/journal.pbio.3000848 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1048.xml |
| 035 | |a (DE-627)NLM314707921 | ||
| 035 | |a (NLM)32898131 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Tolkatchev, Dmitri |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Leiomodin creates a leaky cap at the pointed end of actin-thin filaments |
| 264 | 1 | |c 2020 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 20.10.2020 | ||
| 500 | |a Date Revised 14.12.2021 | ||
| 500 | |a published: Electronic-eCollection | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Improper lengths of actin-thin filaments are associated with altered contractile activity and lethal myopathies. Leiomodin, a member of the tropomodulin family of proteins, is critical in thin filament assembly and maintenance; however, its role is under dispute. Using nuclear magnetic resonance data and molecular dynamics simulations, we generated the first atomic structural model of the binding interface between the tropomyosin-binding site of cardiac leiomodin and the N-terminus of striated muscle tropomyosin. Our structural data indicate that the leiomodin/tropomyosin complex only forms at the pointed end of thin filaments, where the tropomyosin N-terminus is not blocked by an adjacent tropomyosin protomer. This discovery provides evidence supporting the debated mechanism where leiomodin and tropomodulin regulate thin filament lengths by competing for thin filament binding. Data from experiments performed in cardiomyocytes provide additional support for the competition model; specifically, expression of a leiomodin mutant that is unable to interact with tropomyosin fails to displace tropomodulin at thin filament pointed ends and fails to elongate thin filaments. Together with previous structural and biochemical data, we now propose a molecular mechanism of actin polymerization at the pointed end in the presence of bound leiomodin. In the proposed model, the N-terminal actin-binding site of leiomodin can act as a "swinging gate" allowing limited actin polymerization, thus making leiomodin a leaky pointed-end cap. Results presented in this work answer long-standing questions about the role of leiomodin in thin filament length regulation and maintenance | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Actin Capping Proteins |2 NLM | |
| 650 | 7 | |a Actins |2 NLM | |
| 650 | 7 | |a Cytoskeletal Proteins |2 NLM | |
| 650 | 7 | |a LMOD2 protein, human |2 NLM | |
| 650 | 7 | |a Lmod2 protein, rat |2 NLM | |
| 650 | 7 | |a Microfilament Proteins |2 NLM | |
| 650 | 7 | |a Muscle Proteins |2 NLM | |
| 650 | 7 | |a leiomodin protein, mouse |2 NLM | |
| 700 | 1 | |a Smith, Garry E |c Jr |e verfasserin |4 aut | |
| 700 | 1 | |a Schultz, Lauren E |e verfasserin |4 aut | |
| 700 | 1 | |a Colpan, Mert |e verfasserin |4 aut | |
| 700 | 1 | |a Helms, Gregory L |e verfasserin |4 aut | |
| 700 | 1 | |a Cort, John R |e verfasserin |4 aut | |
| 700 | 1 | |a Gregorio, Carol C |e verfasserin |4 aut | |
| 700 | 1 | |a Kostyukova, Alla S |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t PLoS biology |d 2003 |g 18(2020), 9 vom: 08. Sept., Seite e3000848 |w (DE-627)NLM12680690X |x 1545-7885 |7 nnns |
| 773 | 1 | 8 | |g volume:18 |g year:2020 |g number:9 |g day:08 |g month:09 |g pages:e3000848 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1371/journal.pbio.3000848 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 18 |j 2020 |e 9 |b 08 |c 09 |h e3000848 | ||