Key result
EPR spectroscopy revealed that the UN2A domain of titin adopts a compact, stable three-helix bundle fold that undergoes no significant conformational change upon binding to CARP.
Why the study?
The titin UN2A domain three-dimensional structure was previously modelled in isolation, leaving its conformation upon binding to CARP uncharacterized experimentally.
The UN2A domain of titin acts as a stable, rigid-body scaffold when binding to CARP, providing structural insights into the regulation of sarcomeric stiffness.
Structural insights into titin-CARP binding may inform sarcomeric stiffness models; leaves open in vivo validation.
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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Stehle et al. (2023) studied this question. CARP binding to Titin UN2A vs. Absence of CARP was evaluated on Conformational change of UN2A domain upon CARP binding. EPR spectroscopy revealed that the UN2A domain of titin adopts a compact, stable three-helix bundle fold that undergoes no significant conformational change upon binding to CARP.
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