THESIS
2021
1 online resource (xiv, 116 pages) : illustrations (some color)
Abstract
IQSEC family proteins are synaptic scaffold proteins responsible for synaptic
transmission and long-term depression. Genetic variants of IQSEC2 cause a variety of
neuronal disorders, including intellectual disability, autism and epilepsy. The Arf-GEF
activity of IQSEC2 has been demonstrated to regulate the endocytosis of AMPA
receptors and long-term depression. However, the molecular mechanism underlying
IQSEC2’s function in brains is poorly understood. Here we discover that without Ca
2+,
CaM/IQ complex could directly bind to Sec7PH supramodule and further inhibit its
GEF activity. After Ca
2+ addition, CaM/IQ complex dissociates from the Sec7PH and
activates the Sec7 GEF activity. Crystallographic studies showed that apo-CaM/IQ
shares an overlapped binding site with Arf1 in Sec7 domain....[
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IQSEC family proteins are synaptic scaffold proteins responsible for synaptic
transmission and long-term depression. Genetic variants of IQSEC2 cause a variety of
neuronal disorders, including intellectual disability, autism and epilepsy. The Arf-GEF
activity of IQSEC2 has been demonstrated to regulate the endocytosis of AMPA
receptors and long-term depression. However, the molecular mechanism underlying
IQSEC2’s function in brains is poorly understood. Here we discover that without Ca
2+,
CaM/IQ complex could directly bind to Sec7PH supramodule and further inhibit its
GEF activity. After Ca
2+ addition, CaM/IQ complex dissociates from the Sec7PH and
activates the Sec7 GEF activity. Crystallographic studies showed that apo-CaM/IQ
shares an overlapped binding site with Arf1 in Sec7 domain. NMR and ITC assays
demonstrate that Ca
2+ indeed induces conformational changes of CaM/IQ complex
which prevents the Ca
2+-CaM/IQ binding to Sec7PH. This kind of Ca
2+ regulation
also works for all IQSEC family proteins. Several genetic variants in IQSEC2 linked
with intellectual disability could be explained through our crystal structure.
Thus, IQ motif can sense Ca
2+ signal through CaM and then regulate Sec7 GEF
activity. Due to different localization of IQSEC family proteins, a novel and general
mechanism of Ca
2+ regulation occurs in both excitatory and inhibitory postsynapses.
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