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<p>The truncated constitutive active form of protein kinase C (PKC) called protein kinase M (PKM) plays a role in long-term memory maintenance in vertebrate and invertebrate models. Previously we have shown that the <i>Aplysia</i> Kidney/Brain protein (KIBRA) stabilizes the atypical PKM Apl III, but not the classical PKM Apl I in <i>Aplysia</i> neurons. Expression of <i>Aplysia</i> KIBRA with changes in the proposed atypical PKM binding site does not stabilize PKM Apl III and erases forms of plasticity supported by PKM Apl III. Here, we have examined biomolecular fluorescence complementation (BIFC) between KIBRA variants and PKM Apl III in <i>Aplysia</i> neurons. These KIBRA variants include: the KIBRA with changes in the proposed atypical binding site noted above; a splicing variant that stabilizes PKM Apl I, but not PKM Apl III; and several mutations identified in mammalian WW and C2 domain containing protein 3 (WWC3, a member of the chordate-specific expansion of the KIBRA family) associated with cancer or neurodevelopmental disorders. Surprisingly, we find that some KIBRA variants show BIFC with PKM Apl III but do not stabilize PKM Apl III. We used models of protein-protein interactions (AlphaFold 3) to gain insights into the discrepancy between BIFC and stabilization of PKMs by KIBRA and KIBRA variants and suggest a model where stabilization is linked to stable inhibition of PKMs by KIBRA.</p>

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Generating models for isoform-specific PKM-KIBRA interactions with BIFC, stabilization and AlphaFold 3

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月19日

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  • Edna Amoah,
  • Tyler W. Dunn,
  • Larissa Ferguson,
  • Kristel Betriu Diaz,
  • Connor O’Donnell,
  • Joachim Kremerskoten,
  • Wayne S. Sossin

摘要

The truncated constitutive active form of protein kinase C (PKC) called protein kinase M (PKM) plays a role in long-term memory maintenance in vertebrate and invertebrate models. Previously we have shown that the Aplysia Kidney/Brain protein (KIBRA) stabilizes the atypical PKM Apl III, but not the classical PKM Apl I in Aplysia neurons. Expression of Aplysia KIBRA with changes in the proposed atypical PKM binding site does not stabilize PKM Apl III and erases forms of plasticity supported by PKM Apl III. Here, we have examined biomolecular fluorescence complementation (BIFC) between KIBRA variants and PKM Apl III in Aplysia neurons. These KIBRA variants include: the KIBRA with changes in the proposed atypical binding site noted above; a splicing variant that stabilizes PKM Apl I, but not PKM Apl III; and several mutations identified in mammalian WW and C2 domain containing protein 3 (WWC3, a member of the chordate-specific expansion of the KIBRA family) associated with cancer or neurodevelopmental disorders. Surprisingly, we find that some KIBRA variants show BIFC with PKM Apl III but do not stabilize PKM Apl III. We used models of protein-protein interactions (AlphaFold 3) to gain insights into the discrepancy between BIFC and stabilization of PKMs by KIBRA and KIBRA variants and suggest a model where stabilization is linked to stable inhibition of PKMs by KIBRA.