Key result
Protein binder B86 binds titin M10 with ~1.8 µM affinity and localizes to the sarcomere M-band.
De novo-designed protein binders can be successfully generated in silico to specifically target and visualize sarcomeric proteins like titin in situ, offering an alternative to traditional antibodies for fluorescence microscopy.
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May enable antibody-free titin imaging in research; extends de novo design to sarcomeric proteins but leaves clinical translation open.
Advances in the generation of proteins in silico has enabled the efficient design of target-specific binders. Here, we demonstrate the use of a de novo-designed protein targeting the C-terminal domain, M10, of the giant muscle protein titin in situ and image its localisation using fluorescence microscopy, a widely used technique that has relied on antibodies or similar binders to identify the presence and location of targets in their native environment. Confocal microscopy of muscle sections shows the binder localizes to the M-band of the sarcomere – where M10 is found – and fails to label muscle in competition experiments and in mutant muscle where M10 is absent. This new approach to identifying the presence and location of targets in their native environment avoids the need to generate binders in vivo or in vitro which can have technical, financial and ethical challenges.
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Rees et al. (2026) studied this question. De novo-designed titin binder B86 was evaluated on Binding affinity (Kd) to titin domain M10 (Kd of 1.80 ± 0.21 µM). The de novo-designed protein binder B86 specifically binds to the M10 domain of titin in vitro with a Kd of 1.80 µM and successfully localizes to the M-band of the sarcomere in fluorescence microscopy.
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