THESIS
2018
xviii, 160 pages : illustrations (some color) ; 30 cm
Abstract
WW domain is one of the smallest protein domains, and is capable of mediating protein-protein interaction through binding to Pro-rich sequences. WW domain-containing proteins and their complexes have been implicated in several major signaling cascades including Hippo tumor suppressor pathway, slit diaphragm formation and maintenance and neuronal synaptic signaling. The canonical binding mode of WW domain provides a simple and basic interaction mechanism with its ligands. However, such low specific bindings apparently do not match with often very specific functions of WW domain-containing proteins or their targets.
During the first part of this thesis, combining biochemical and structural analysis, this thesis work revealed three previously unrecognized tandem WW domain-mediated target...[
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WW domain is one of the smallest protein domains, and is capable of mediating protein-protein interaction through binding to Pro-rich sequences. WW domain-containing proteins and their complexes have been implicated in several major signaling cascades including Hippo tumor suppressor pathway, slit diaphragm formation and maintenance and neuronal synaptic signaling. The canonical binding mode of WW domain provides a simple and basic interaction mechanism with its ligands. However, such low specific bindings apparently do not match with often very specific functions of WW domain-containing proteins or their targets.
During the first part of this thesis, combining biochemical and structural analysis, this thesis work revealed three previously unrecognized tandem WW domain-mediated target recognition mode. Kibra is known to be memory related but the molecular mechanism is poorly understood. We revealed that Kibra WW tandem binds to a highly enriched postsynaptic protein Dendrin with super high binding affinity and specificity. To assess its synaptic function, based on our structural understanding we designed a highly potent Kibra WW tandem inhibitor, which impairs synaptic plasticity and learning and memory performance in mice. We also demonstrated that a Kibra disease mutation has defects in binding to Dendrin. These data indicate that Kibra controls memory via binding to Dendrin.
For the second part of this thesis, we revealed that MAGI WW tandem can adapt to diverse ligand binding mode. MAGI WW tandem binds to a two PY motif-containing sequence of RapGEF2, and the linker sequence between the two PY-motifs are critical for forming the WW tandem supramodule. In contrast, the MAGI WW tandem binds to IQSEC3 with a distinct mode with one WW domain binds to a PY-motif and another WW domain engages a poly-Proline sequence, indicating that type I WW domains not only bind to the PY-motifs, but can also recognize poly-Porline sequences.
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