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 Ca²⁺, CaM/IQ complex could directly bind to Sec7PH supramodule and further inhibit its GEF activity. After Ca²⁺ 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....[ Read more ]

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 Ca²⁺, CaM/IQ complex could directly bind to Sec7PH supramodule and further inhibit its GEF activity. After Ca²⁺ 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 Ca²⁺ indeed induces conformational changes of CaM/IQ complex which prevents the Ca²⁺-CaM/IQ binding to Sec7PH. This kind of Ca²⁺ 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 Ca²⁺ signal through CaM and then regulate Sec7 GEF activity. Due to different localization of IQSEC family proteins, a novel and general mechanism of Ca²⁺ regulation occurs in both excitatory and inhibitory postsynapses.