Ca2+-induced release of IQSEC2/BRAG1 autoinhibition under physiological and pathological conditions

Abstract

IQSEC2 (aka BRAG1) is a guanine nucleotide exchange factor (GEF) highly enriched in synapses. As a top neurodevelopmental disorder risk gene, numerous mutations are identified in Iqsec2 in patients with intellectual disabilities accompanied by other developmental, neurological, and psychiatric symptoms, though with poorly understood underlying molecular mechanisms. The atomic structures of IQSECs, together with biochemical analysis, presented in this study reveal an autoinhibition and Ca2+-dependent allosteric activation mechanism for all IQSECs and rationalize how each identified Iqsec2 mutation can alter the structure and function of the enzyme. Transgenic mice modeling two pathogenic variants of Iqsec2 (R359C and Q801P), with one activating and the other inhibiting the GEF activity of the enzyme, recapitulate distinct clinical phenotypes in patients. Our study demonstrates that different mutations on one gene such as Iqsec2 can have distinct neurological phenotypes and accordingly will require different therapeutic strategies.

Interrogation and validation of the interactome of neuronal Munc18-interacting Mint proteins with AlphaFold2

“…S1), AlphaFold2 does not predict a confident interaction with these proteins (not shown), suggesting their sequences are less optimized for binding. The IQSEC1 and IQSEC2 proteins are Ca + /CaM-regulated synaptic proteins that can activate all members of the ARF GTPase family (Bai et al, 2023;Peurois et al, 2017;Um, 2017), and are mutated in neuronal developmental disorders including X-linked intellectual disability with early onset epileptic encephalopathy (Ansar et al, 2019;Zerem et al, 2016). Notably, the IQSEC1 protein was previously shown to bind a short Tyr-containing sequence in the C-terminus of the GluA2 AMPA receptor via the PH domain (Scholz et al, 2010), and we speculate that Mint2 and GluA2 may utilize the same binding site in the IQSEC proteins.…”

BRAG about (s)lots

“…BRAG1 knockout mice display autistic-like deficits also consistent with impaired LTD ( 9 ). Yet, until this issue’s report by Bai and colleagues ( 10 ), it had not been determined how BRAG1’s constitutive GEF activity is regulated, or precisely how these clinical mutations lead to impaired GEF activity and subsequent synaptic and cognitive deficits.…”

“…Because alterations in the IQ and Sec7 domains have overlapping phenotypes, Bai et al ( 10 ) first sought to understand the nature of their interactions. They found that in the absence of Ca 2+ , the Apo-CaM/IQ complex tightly binds the Sec7-PH tandem resulting in a closed conformation, which silences Sec7 catalytic activity.…”

“…Bai et al ( 10 ) then examined two known pathogenic IQ mutations, R359C and A350V/D. These mutations weakened the interaction between IQ and Apo-CaM but had less impact on the Ca 2+ -CaM binding.…”

“…In summary, Bai et al ( 10 ) provide a huge step forward in our understanding of IQSEC2/BRAG1 function and pathology, which opens the door to generating personalized precision treatment strategies.…”