Kibra Modulates Learning and Memory via Binding to Dendrin

• Published in: Cell reports (Cambridge) Vol. 26; no. 8; pp. 2064 - 2077.e7
• Main Authors: Ji, Zeyang, Li, Hao, Yang, Zhou, Huang, Xian, Ke, Xiao, Ma, Sehui, Lin, Zhijie, Lu, Youming, Zhang, Mingjie
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19.02.2019; Elsevier
• Subjects: Animals; Binding Sites; Cells, Cultured; Dendrin; HEK293 Cells; HeLa Cells; Humans; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors; Intracellular Signaling Peptides and Proteins - chemistry; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Kibra; learning and memory; Male; Mice; Mice, Inbred C57BL; Mutation; Nerve Tissue Proteins - metabolism; Phosphoproteins - antagonists & inhibitors; Phosphoproteins - chemistry; Phosphoproteins - genetics; Phosphoproteins - metabolism; Post-Synaptic Density - metabolism; Protein Binding; psychiatric disorder; scaffold protein; Spatial Learning; synaptic complex; synaptic transmission; tandem repeats; Tourette syndrome; WW domains; psychiatric disorder; Kibra; learning and memory; tandem repeats; scaffold protein; synaptic transmission; WW domains; Tourette syndrome; synaptic complex; Dendrin
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.01.097

Kibra is a synaptic scaffold protein regulating learning and memory. Alterations of Kibra-encoding gene WWC1 cause various neuronal disorders, including Alzheimer’s disease and Tourette syndrome. However, the molecular mechanism underlying Kibra’s function in neurons is poorly understood. Here we discover that Kibra, via its N-terminal WW12 tandem domains, binds to a postsynaptic density enriched protein, Dendrin, with a nanomolar dissociation constant. On the basis of the structure of Kibra WW12 in complex with Dendrin PY motifs, we developed a potent peptide inhibitor capable of specifically blocking the binding between Kibra and Dendrin in neurons. Systematic administration of the inhibitory peptide attenuated excitatory synaptic transmission, completely blocked long-term potentiation induction, and impaired spatial learning and memory. A Kibra mutation found in Tourette syndrome patients causes defects in binding to Dendrin. Thus, Kibra can modulate spatial learning and memory via binding to Dendrin. [Display omitted] •Kibra WW tandem domains bind to Dendrin with low-nanomolar affinity•Structure of Kibra WW domains bound to Dendrin PY motifs reveals the binding mechanism•Disruption of the Kibra/Dendrin interaction impairs learning and memory in mice•A Kibra mutation associated with Tourette syndrome causes defects in Dendrin binding Ji et al. report that the memory-related molecule Kibra, via its WW tandem domains, specifically binds to the synaptic protein Dendrin with a low-nanomolar dissociation constant to modulate spatial learning and memory.