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. 2024 Oct 17;31(10):1815-1826.e5.
doi: 10.1016/j.chembiol.2024.06.016. Epub 2024 Jul 26.

Dissecting the neuroprotective interaction between the BH4 domain of BCL-w and the IP3 receptor

Sophia X Tang  1 , Christina M Camara  1 , Joy A Franco  2 , Maria F Pazyra-Murphy  2 , Yihang Li  2 , Marina Godes  1 , Benjamin M Moyer  1 , Gregory H Bird  1 , Rosalind A Segal  3 , Loren D Walensky  4
Affiliations

Dissecting the neuroprotective interaction between the BH4 domain of BCL-w and the IP3 receptor

Sophia X Tang et al. Cell Chem Biol. .

Abstract

BCL-w is a BCL-2 family protein that promotes cell survival in tissue- and disease-specific contexts. The canonical anti-apoptotic functionality of BCL-w is mediated by a surface groove that traps the BCL-2 homology 3 (BH3) α-helices of pro-apoptotic members, blocking cell death. A distinct N-terminal portion of BCL-w, termed the BCL-2 homology 4 (BH4) domain, selectively protects axons from paclitaxel-induced degeneration by modulating IP3 receptors, a noncanonical BCL-2 family target. Given the potential of BCL-w BH4 mimetics to prevent or mitigate chemotherapy-induced peripheral neuropathy, we sought to characterize the interaction between BCL-w BH4 and the IP3 receptor, combining "staple" and alanine scanning approaches with molecular dynamics simulations. We generated and identified stapled BCL-w BH4 peptides with optimized IP3 receptor binding and neuroprotective activities. Point mutagenesis further revealed the sequence determinants for BCL-w BH4 specificity, providing a blueprint for therapeutic targeting of IP3 receptors to achieve neuroprotection.

Keywords: BCL-2 family; BCL-w; BH4 domain; IP3 receptor; axon degeneration; chemotherapy induced peripheral neuropathy; neuroprotection; paclitaxel; stapled peptide.

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Conflict of interest statement

Declaration of interests M.F.P.-M., G.H.B., R.A.S., and L.D.W. are named co-inventors on international patent application WO 2018/039545 (and associated patent applications and granted national patents) related to this work.

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