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Submission Date
Fall 2024
Abstract
Due to the complexity of the brain, the underlying mechanisms of most neurobiological diseases have yet to be completely uncovered, prompting the use of more innovative tools in current research. Designing 3D printed protein models has shown promising results in facilitating the understanding of protein dynamics by allowing scientists to analyze protein binding and folding at a 3-dimensional level. Kidney and Brain Expressed Protein (KIBRA) is a synaptic scaffold protein commonly found in brain regions associated with learning and memory. Expressed highly in the hippocampus, KIBRA is crucial for synaptic plasticity, but beyond its role in memory, it is also involved in the Hippo signaling pathway, which is a tissue growth regulator that plays a key role in the regulation of cell proliferation, survival, apoptosis, and stem cell renewal. Since KIBRA influences processes related to beta-amyloid, a protein associated with Alzheimer’s pathology, it is a potential target for treatments aiming to slow the rate of cognitive decline that characterizes this disease. KIBRA displays a tryptophan-rich WW12 domain, a supramodule of the W1 and W2 domain with higher stability and higher binding characteristics due to the interactions between an inter-domain linker and an α-helix extension. This domain selectively binds to molecules containing a PPxY motif such as dendrin and PTPN14. Dendrin is a synaptic protein containing a unique sequence of PY motifs which attract it to the WW12 tandem of KIBRA for proper functioning of learning and memory. PTPN14 (Protein Tyrosine Phosphatase, Non-receptor type 14), a peptide known to influence angiogenesis and tumor suppression, interacts with KIBRA within the Hippo signaling pathway, playing complementary roles in regulating cellular growth, adhesion, and migration. The proline rich PY motif of PTPN14 is known to specifically bind to the WW12 domain of KIBRA. Research has also shown that KIBRA additionally contains a PKMζ binding domain that allows PKMζ (Protein Kinase MZeta), a protein involved in potentiating synaptic transmission, to bind and avoid degradation, further increasing the efficacy of spatial long-term memory formation and maintenance, as well as skilled motor learning. Since there are no current PDB IDs containing a full structure of KIBRA, AlphaFold 3, a Nobel Prize winning AI system for 3D protein modeling, was used to predict a model of KIBRA bound to the PY-containing binding domains of short sequences of dendrin and PTPN14, whose sequences were isolated from PDB 6J69 and PDB 6JJW respectively. The resulting predicted model was 3-D printed to highlight the WW12 domain and the PKMζ binding domain of KIBRA, emphasizing known amino acid mutation locations on KIBRA and its binding partners that can cause changes in their binding affinity, ultimately affecting disease formation and progression.
Recommended Citation
Mehra, Aniruddh; Weber, Anna Maria; and Mekala, Chandralekha Sai, "Modeling the Binding of Dendrin and PTPN14 to KIBRA" (2024). Protein Modeling Reports. 21.
https://nsuworks.nova.edu/protein_modeling_reports/21
Modeling the Binding of Dendrin and PTPN14 to KIBRA Presentation
KIBRA-poster.pdf (1333 kB)
Modeling the Binding of Dendrin and PTPN14 to KIBRA Poster