Abstract
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.
Highlights
The complexity of striated muscle is defined by the intricate organization of its components [1]
matrix metalloproteinases (MMPs)-2 was fragmented by MMP-2 in a concentration-dependent manner, which was inhibited in the presence of SMYD2 that binds to the N2A domain
It is notable that muscle ankyrin repeat proteins (MARPs) were shown to be dispensable in heart development and hypertrophic responses [59]
Summary
The complexity of striated muscle is defined by the intricate organization of its components [1]. MARPs are known as transcription modulators activated by stress in striated muscle [22] Their binding interactions to N2A titin connect the N2A insertion as a stress-sensing or responsive area of titin [15]. 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. We will appraise it in terms of its proteolysis by proteases in the context of the stress response or protein quality control It will be concluded with remarks on the functional importance of the N2A domain’s interactions in striated muscle
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