Structures of wild-type and selected CMT1X mutant connexin 32 gap junction channels and hemichannels

Qi, C.; Lavriha, P.; Bayraktar, E.; Vaithia, A.; Schuster, D.; Pannella, M.; Sala, V.; Picotti, P.; Bortolozzi, M.; Korkhov, V. M.

doi:10.1101/2023.03.08.531661

bioRxiv · 10.1101/2023.03.08.531661

Structures of wild-type and selected CMT1X mutant connexin 32 gap junction channels and hemichannels

Qi, C.·Lavriha, P.·Bayraktar, E.·Vaithia, A.·Schuster, D.·Pannella, M.·Sala, V.·Picotti, P.·Bortolozzi, M.·Korkhov, V. M.

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Abstract

In myelinating Schwann cells, communication between myelin layers is mediated by gap junction channels (GJC) formed by docked connexin 32 hemichannels (HCs). Mutations in Cx32 cause the X-linked Charcot-Marie-Tooth disease (CMT1X), a degenerative neuropathy with no cure. A molecular link between Cx32 dysfunction and CMT1X pathogenesis is still missing. Here, we describe the high resolution cryo-EM structures of the Cx32 GJC and HC, along with two CMT1X-linked mutants, W3S and R22G. While the structures of wild-type and mutant GJCs are virtually identical, the HCs show a major difference: in the W3S and R22G mutant HCs, the N-terminal helix partially occludes the pore, consistent with an impaired HC activity. Our results suggest that HC dysfunction may be involved in the pathogenesis of CMT1X. One-Sentence SummaryConnexin 32 channel structures reveal a gating helix defect in CMT1X disease-associated mutant hemichannels

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Qi, C., Lavriha, P., Bayraktar, E., Vaithia, A., Schuster, D., Pannella, M., Sala, V., Picotti, P., Bortolozzi, M., Korkhov, V. M.. 2023-03-10. Structures of wild-type and selected CMT1X mutant connexin 32 gap junction channels and hemichannels. https://doi.org/10.1101/2023.03.08.531661

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