Exon Inclusion Modulates Conformational Plasticity and Autoinhibition of the Intersectin 1 SH3A Domain

Microexon alternative splicing of small GTPase regulators: Implication in central nervous system diseases

“…During the differentiation of mouse embryonic stem cells to glutamatergic neurons, 151 microexons undergo AS which are enriched in small GTPases pathway, such as Dock7, Dock9, Robo1/2, Git2, and Itsn1 (Irimia et al, 2014). Later studies using in vivo and in vitro models showed that the splicing of microexons could influence protein–protein interactions and the activity of the small GTPases, impacting CNS development (Gerth et al, 2019; Johnson et al, 2019). For instance, as mentioned previously in the review, during the CNS development, Robo1/2 microexon6/6b is alternatively spliced, which confers differential activities of RAC1 and CDC42 (Johnson et al, 2019).…”

“…For instance, as mentioned previously in the review, during the CNS development, Robo1/2 microexon6/6b is alternatively spliced, which confers differential activities of RAC1 and CDC42 (Johnson et al, 2019). Another example is intersectin1 (ITSN1), a Cdc42 GEF protein implicated in clathrin‐mediated endocytosis in the synapse, which undergoes microexon AS within its SH3 domain (Gerth et al, 2019; Tsyba et al, 2008). Specifically, the inclusion of the 15 nucleotide microexon in ITSN1 changes the protein binding affinity with synaptic interacting partners, including SYN1, CYFIP2, and WIPF3.…”