KH domain-containing, RNA-binding, signal transduction-associated protein 3

KHDRBS3 (KH domain-containing, RNA-binding, signal transduction-associated protein 3) is an RNA-binding protein that regulates alternative splicing and influences mRNA splice site selection. It binds preferentially to AU-rich motifs and plays roles in the splicing of functionally important transcripts, including vascular endothelial growth factor and neurexins (NRXN1–3), which are critical for synaptic targeting and glutamatergic synapse function (UniProt: O75525). The protein's RNA-binding activities are modulated by tyrosine kinase PTK6 and may also regulate splicing of other neuronal transcripts such as KHDRBS2.

KHDRBS3 is primarily relevant to neuronal function and synaptic plasticity. Its regulation of neurexin alternative splicing connects it to postsynaptic partner recognition and neuronal glutamatergic signaling, processes central to brain development and maintenance (UniProt: O75525).

KHDRBS3 is downregulated in Alzheimer's disease brain tissue, with a mean log2 fold-change of −1.11 in post-mortem AD brain compared to age-matched controls across proteomics analysis (Chaparral AD proteomics). This downregulation may impair the synaptic regulatory functions mediated by KHDRBS3-dependent alternative splicing, potentially contributing to synaptic dysfunction observed in AD pathology.