9M46

Crystal structure of IQSEC2 CC domain

Summary for 9M46

• Entry DOI: 10.2210/pdb9m46/pdb
• Descriptor: IQ motif and SEC7 domain-containing protein 2 (2 entities in total)
• Functional Keywords: coiled-coil, signaling protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 31390.07

Authors

Bai, G.,Cai, Q.,Zhang, M. (deposition date: 2025-03-03, release date: 2025-10-22, Last modification date: 2025-11-05)

Primary citation

Bai, G.,Huang, R.,Nan, X.,Zhuang, M.,Wu, M.,Lian, Y.,Cai, Q.,Tian, H.,Lu, Y.,Li, H.,Zhang, M.
IQSEC2/BRAG1 may modulate postsynaptic density assembly through Ca2+-induced phase separation.
J.Cell Biol., 224:-, 2025

PubMed Abstract: IQSEC2, a high-confidence neurodevelopmental disorder risk gene product, is essential for neuronal development and synaptic plasticity. Previous studies established that IQSEC2 dynamically regulates synaptic signaling via Ca2+-dependent release of autoinhibition. In this study, using in vivo mouse models and in vitro biochemistry approaches, we discover that IQSEC2 orchestrates postsynaptic density assembly and dynamics via Ca2+-triggered phase separation. Mechanistically, Ca2+-induced conformational opening leads to phase separation-mediated condensation of IQSEC2 at synapses, a process that requires the N-terminal multimerization domain and intrinsically disordered regions of IQSEC2. We identified a single-point mutation, F367A, in IQSEC2, which exhibits constitutive activity by structurally mimicking the Ca2+-activated state of the WT protein. Mice carrying the Iqsec2_F367A mutation have elevated basal synaptic transmission and impaired activity-dependent plasticity assayed in hippocampal neurons and spatial learning deficits. Thus, IQSEC2 can bidirectionally modulate synaptic strengths via Ca2+-dependent phase separation, and dysregulation of phase separation may be a contributing factor in IQSEC2-related neurodevelopmental disorders.

PubMed: 41123449
DOI: 10.1083/jcb.202503076

Experimental method

X-RAY DIFFRACTION (1.77 Å)