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bioRxiv · 10.64898/2026.10.26.761849

Heat-dependent engagement of a buried mitophagy motif in prohibitin 2

Nan, J.·Yang, X.·Lin, Y.·Shao, Z.·Wang, X.·Wang, B.·Zhao, D.·Liu, B.
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Abstract

Mitophagy receptors are generally switched on by upstream enzymes rather than by the receptor itself. Whether a receptor can instead respond directly to a physical stimulus has not been established. Here we show that a second LC3-interacting region (LIR) in prohibitin 2 (PHB2) is regulated by temperature. It lies in a marginally stable helix that holds its two anchor residues about 5 angstrom apart, whereas a bound LIR spans about 9 angstrom. Replica-scaling simulations showed that this helix, but not a matched control from the same protein under identical scaling, samples that geometry; purified PHB2 bound ATG8-family proteins only at 313 K and above. Substitutions designed from this geometry to stabilise (K253A/R255A) or destabilise (I254G) the helix altered binding, mitochondrial recruitment and respiration in PHB2-null cardiomyocytes. Mice carrying the stabilising substitutions in cardiomyocytes sustained greater cardiac injury during heat stroke despite matched thermal load and comparable systemic injury. Motif accessibility may therefore be a regulated variable rather than a fixed property of a fold.

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Nan, J., Yang, X., Lin, Y., Shao, Z., Wang, X., Wang, B., Zhao, D., Liu, B.. 2026-10-28. Heat-dependent engagement of a buried mitophagy motif in prohibitin 2. https://doi.org/10.64898/2026.10.26.761849

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