Structural dynamics of the intrinsically disordered linker region of cardiac troponin T DOI Creative Commons
Jasmine Cubuk, Lina Greenberg,

Akiva E. Greenberg

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 31, 2024

The cardiac troponin complex, composed of troponins I, T, and C, plays a central role in regulating the calcium-dependent interactions between myosin thin filament. Mutations can cause cardiomyopathies; however, it is still major challenge to connect how changes sequence affect troponin's function. Recent high-resolution structures filament revealed critical insights into structure-function relationship troponin, but there remain large, unresolved segments including troponin-T linker region that hotspot for cardiomyopathy mutations. This predicted be intrinsically disordered, with behaviors are not well described by traditional structural approaches; this proposal has been experimentally verified. Here, we used combination single-molecule Förster resonance energy transfer (FRET), molecular dynamics simulations, functional reconstitution assays investigate region. We show context both isolated fully regulated behaves as dynamic, disordered undergoes polyampholyte expansion presence high salt distinct conformational during assembly complex. also examine ΔE160 hypertrophic mutation demonstrate does linker, rather allosterically affects other complex subunits, leading increased contractility. Taken together, our data clearly importance disorder within provide new mechanisms driving pathogenesis cardiomyopathies.

Language: Английский

Direct prediction of intermolecular interactions driven by disordered regions DOI Creative Commons
Garrett M. Ginell, Ryan J. Emenecker, Jeffrey M. Lotthammer

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 3, 2024

ABSTRACT Intrinsically disordered regions (IDRs) are critical for a wide variety of cellular functions, many which involve interactions with partner proteins. Molecular recognition is typically considered through the lens sequence-specific binding events. However, growing body work has shown that IDRs often interact partners in manner does not depend on precise order amino acid order, instead driven by complementary chemical leading to bound-state complexes. Despite this emerging paradigm, we lack tools describe, quantify, predict, and interpret these types structurally heterogeneous from underlying sequences. Here, repurpose physics developed originally molecular simulations develop an approach predicting intermolecular between Our enables direct prediction phase diagrams, identification chemically-specific interaction hotspots IDRs, route test mechanistic hypotheses regarding IDR function context recognition. We use our examine range systems questions highlight its versatility applicability.

Language: Английский

Citations

16
Structural dynamics of the intrinsically disordered linker region of cardiac troponin T DOI Creative Commons
Jasmine Cubuk, Lina Greenberg,

Akiva E. Greenberg

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 31, 2024

The cardiac troponin complex, composed of troponins I, T, and C, plays a central role in regulating the calcium-dependent interactions between myosin thin filament. Mutations can cause cardiomyopathies; however, it is still major challenge to connect how changes sequence affect troponin's function. Recent high-resolution structures filament revealed critical insights into structure-function relationship troponin, but there remain large, unresolved segments including troponin-T linker region that hotspot for cardiomyopathy mutations. This predicted be intrinsically disordered, with behaviors are not well described by traditional structural approaches; this proposal has been experimentally verified. Here, we used combination single-molecule Förster resonance energy transfer (FRET), molecular dynamics simulations, functional reconstitution assays investigate region. We show context both isolated fully regulated behaves as dynamic, disordered undergoes polyampholyte expansion presence high salt distinct conformational during assembly complex. also examine ΔE160 hypertrophic mutation demonstrate does linker, rather allosterically affects other complex subunits, leading increased contractility. Taken together, our data clearly importance disorder within provide new mechanisms driving pathogenesis cardiomyopathies.

Language: Английский

Citations

0