Molecular Characterisation of Titin N2A and Its Binding of CARP Reveals a Titin/Actin Cross-linking Mechanism

Zhou, Tiankun; Fleming, Jennifer R.; Lange, Stephan; Hessel, Anthony L.; Bogomolovas, Julius; Stronczek, Chiara; Grundei, David; Ghassemian, Majid; Biju, Andrea; Börgeson, Emma; Bullard, Belinda; Linke, Wolfgang A.; Chen, Ju; Kovermann, Michael; Mayans, Olga

doi:10.1016/j.jmb.2021.166901

Cited by 27 publications

(60 citation statements)

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“…In addition, the crystal structures of Ig81–Ig83 in tandem have been recently analyzed, showing their distinct structural variations [ 21 ]. Ig82’s conformation was depicted as an N-variable type because its BC and FG loops have a reduced length comparable to exemplary N-variable Ig domains, such as the I9–I11 region of titin [ 36 ].…”

Section: Structural Conformations Of Titin’s N2a Domainmentioning

confidence: 99%

“…Using a combination of NMR approaches and ab initio modeling, a recent report presented a plausible structure for the uN2A insertion [ 21 ]. Unlike the Ig sub-domains of N2A, the model derived for uN2A was not entirely resolved.…”

Section: Structural Conformations Of Titin’s N2a Domainmentioning

confidence: 99%

“…At the I-band, the N2A insertion of titin is regarded as a signaling hub due to its interactions with multiple binding partners involved in different cellular processes [ 18 ]. These binding partners include actin myofilament [ 19 , 20 , 21 ], muscle ankyrin repeat proteins (MARPs) [ 18 , 20 , 21 , 22 ], SET and MYND domain-containing protein 2 (SMYD2) [ 23 , 24 ], methylated HSP90 [ 23 , 25 ], proteases such as p94/calpain 3 and μ-calpain/calpain 1 [ 18 , 24 ], and a contraction modulator, calcium (Ca 2+ ) [ 19 , 26 ]. The binding of N2A titin to these partners establishes connections between titin and biological cascades elicited by the binding partners.…”

Section: Introductionmentioning

confidence: 99%

“…Recently, SMYD2’s binding interaction to N2A was reported to help protect N2A or titin from proteolysis by proteases [ 24 ]. The N2A–actin-filament interaction mediated by CARP was found to be important to regulate the contractile force in the skeletal muscle [ 20 , 21 ]. These observations collectively highlight the significance of the N2A insertion for modulating titin’s activity and, by extension, sarcomere integrity, which brings a need for appraisal of the N2A domain in light of its interactions and sarcomere maintenance.…”

Section: Introductionmentioning

confidence: 99%

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Titin N2A Domain and Its Interactions at the Sarcomere

Adewale

Ahn

2021

IJMS

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Titin is a giant protein in the sarcomere that plays an essential role in muscle contraction with actin and myosin filaments. However, its utility goes beyond mechanical functions, extending to versatile and complex roles in sarcomere organization and maintenance, passive force, mechanosensing, and signaling. Titin’s multiple functions are in part attributed to its large size and modular structures that interact with a myriad of protein partners. Among titin’s domains, the N2A element is one of titin’s unique segments that contributes to titin’s functions in compliance, contraction, structural stability, and signaling via protein–protein interactions with actin filament, chaperones, stress-sensing proteins, and proteases. Considering the significance of N2A, this review highlights structural conformations of N2A, its predisposition for protein–protein interactions, and its multiple interacting protein partners that allow the modulation of titin’s biological effects. Lastly, the nature of N2A for interactions with chaperones and proteases is included, presenting it as an important node that impacts titin’s structural and functional integrity.

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Section: Structural Conformations Of Titin’s N2a Domainmentioning

confidence: 99%

Section: Structural Conformations Of Titin’s N2a Domainmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Titin N2A Domain and Its Interactions at the Sarcomere

Adewale

Ahn

2021

IJMS

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“…It is also possible that MARP1's impact on titin-based force is not meant to be a sensor at all; instead, the purpose of it is to increase [Ca 2+ ] sensitivity. Titinbased forces strain the thick filament, which has been shown to (Zhou et al, 2021;van der Pijl et al, 2021) suggests that MARP1 tethers titin to the thin filament, functionally shortening titin's free lengths to the stiffer PEVK region, and thus producing more passive tension upon sarcomere stretch. (C) MARP1's function may not only be to increase passive tension, but also to enhance hypertrophic signaling.…”

mentioning

confidence: 99%

Unraveling the mysteries of the titin–N2A signalosome

Hessel¹,

Linke²

2021

Journal of General Physiology

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Titin UN2A Acts as a Stable, Non‐Polymorphic Scaffold in its Binding to CARP

Stehle,

Fleming,

Bauer

et al. 2023

ChemBioChem

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The N2A segment of titin functions as a pivotal hub for signal transduction and interacts with various proteins involved in structural support, chaperone activities, and transcriptional regulation. Notably, the “unique N2A” (UN2A) subdomain has been shown to interact with the stress‐regulated cardiac ankyrin repeat protein (CARP), which contributes to the regulation of sarcomeric stiffness. Previously, the UN2A domain's three‐dimensional structure was modelled based on its secondary structure content identified by NMR spectroscopy, considering the domain in isolation. In this study, we report experimental long‐range distance distributions by electron paramagnetic resonance (EPR) spectroscopy between the three helixes within the UN2A domain linked to the immunoglobulin domain I81 in the presence and absence of CARP. The data confirm the central three‐helix bundle fold of UN2A and show that this adopts a compact and stable conformation in absence of CARP. After binding to CARP, no significant conformational change was observed, suggesting that the UN2A domain retains its structure upon binding to CARP thereby, mediating the interaction approximately as a rigid‐body.

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Molecular Characterisation of Titin N2A and Its Binding of CARP Reveals a Titin/Actin Cross-linking Mechanism

Cited by 27 publications

References 50 publications

Titin N2A Domain and Its Interactions at the Sarcomere

Titin N2A Domain and Its Interactions at the Sarcomere

Unraveling the mysteries of the titin–N2A signalosome

Titin UN2A Acts as a Stable, Non‐Polymorphic Scaffold in its Binding to CARP

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