PKMζ-Kibra Interactions, Molecular Turnover, and Memory

Authors

Changchi Hsieh
David A Cano
Panayiotis Tsokas
James E Cottrell
André Antonio Fenton
Harel Shouval
Todd Charlton Sacktor

Publication Date

3-12-2026

Journal

Molecular Brain

DOI

10.1186/s13041-026-01284-4

PMID

41814337

PMCID

PMC12997682

PubMedCentral® Posted Date

3-12-2026

PubMedCentral® Full Text Version

Post-print

Abstract

How can the molecules that strengthen synaptic connections maintain memory in the face of molecular turnover? Our previous work showed that persistent interaction between the postsynaptic scaffolding protein, KIBRA, and the autonomously active PKC isoform, PKMζ, is crucial for maintaining synaptic long-term potentiation (LTP) and memory lasting at least a month. This duration is longer than the lifespans of individual KIBRA and PKMζ molecules. Biophysical modeling of the interaction suggests oligomers of KIBRA-PKMζ dimers, but not individual dimers or monomers, can overcome molecular turnover by continuously incorporating newly synthesized KIBRA and PKMζ, replacing those that have degraded. Here we used AlphaFold 3 to predict the structures of KIBRA-PKMζ heterodimers and heterohexamers and to examine the sites of action of two different inhibitors of KIBRA-PKMζ interaction that disrupt established late-LTP and long-term memory. The structures predict that the peptide K-ZAP blocks formation of heterodimers, whereas the small molecule ζ-stat prevents PKMζ of one heterodimer from binding a second KIBRA and PKMζ, essential for forming larger oligomeric structures. We show that ζ-stat, like K-ZAP, disrupts 1-month-old spatial memory. Thus, continuous formation of KIBRA-PKMζ oligomers can be a core molecular mechanism driving the persistence of long-term memory in the face of molecular turnover.

Keywords

Protein Kinase C, Animals, Memory, Protein Binding, Intracellular Signaling Peptides and Proteins, Protein Multimerization, Long-Term Potentiation, Models, Molecular, Humans, PKMzeta, PKM-zeta, long-term potentiation (LTP), WWC1

Published Open-Access

yes

Recommended Citation

Hsieh, Changchi; Cano, David A; Tsokas, Panayiotis; et al., "PKMζ-Kibra Interactions, Molecular Turnover, and Memory" (2026). Faculty, Staff and Student Publications. 6529.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/6529