PKMζ-KIBRA interactions, molecular turnover, and memory

Area of Science:

• Neuroscience
• Molecular Biology
• Structural Biology

Background:

• Persistent interaction between KIBRA and PKMζ is vital for synaptic plasticity and memory.
• Molecular turnover challenges the stability of long-term memory.
• Oligomeric structures are hypothesized to overcome molecular degradation.

Purpose of the Study:

• To elucidate the structural basis of KIBRA-PKMζ interactions.
• To investigate the mechanism by which KIBRA-PKMζ oligomers maintain long-term memory.
• To analyze the action of KIBRA-PKMζ interaction inhibitors.

Main Methods:

• Utilized AlphaFold 3 for structural prediction of KIBRA-PKMζ complexes.
• Employed KIBRA-PKMζ inhibitors (K-ZAP and ζ-stat) to study memory disruption.
• Assessed the impact of inhibitors on established spatial memory.

Main Results:

• Predicted structures of KIBRA-PKMζ heterodimers and heterohexamers.
• Identified distinct inhibition mechanisms for K-ZAP (heterodimer formation) and ζ-stat (oligomerization).
• Demonstrated that ζ-stat disrupts 1-month-old spatial memory, similar to K-ZAP.

Conclusions:

• Continual formation of KIBRA-PKMζ oligomers is a key mechanism for long-term memory persistence.
• Structural insights explain how inhibitors impair memory maintenance.
• Oligomerization is crucial for overcoming molecular turnover in memory consolidation.