Fragile X mental retardation protein (FMRP) family members (FMRFM) appear to interact with the TUDOR domain of the survival motor neuron protein in normal conditions; aberrant interactions between the 2 proteins could be a contributing factor to spinal muscular atrophy (SMA) severity, according to a study in the journal Life Science Alliance

Evidence shows that the majority of survival motor neuron (SMN) 1 gene leading to SMA occurs in the TUDOR domain of the SMN protein. This finding suggests that protein-protein interactions within this SMN domain could be implicated in SMA pathogenesis and severity. 

To this date, several SMN TUDOR interacting partners have been identified through conventional coimmunoprecipitation experiments. The authors aimed to increase the current repertoire using the BioID proximity biotinylation approach to discover protein interactions potentially associated with the severity of SMA. Researchers relied on the fusion of SMN to a mutated form of the biotin ligase BirA to detect proteins that could transiently contact SMN and regulate its functions. 


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The analysis led to the detection of over 150 proteins, of which an important percentage were previously SMN partners, and the rest were novel partners such as FMRP, eIF4E2, and CAPRIN1. The results were later validated through coimmunoprecipitation. Results revealed that FMRFM, including FMRP, FXR1, and FXR2, actually interact with endogenous SMN protein.  

To further assess the relationship between SMN and FMRFM and its relevance in SMA, the authors used a panel of SMN mutations associated with SMA, noting that the mutations negatively impacted the FMRFM-SMN interaction, thus confirming that an intact SMN TUDOR domain is required for this interaction. 

To determine whether protein methyltransferases (PRMTs) are involved in the SMN-FMRFM interactions, the authors silenced individual PRMTs, which resulted in the enhancement of the SMN-FMRFM interaction. This suggests arginine-methylated (Rme) proteins could participate in signaling pathways that regulate the SMN-FMRFM interaction and participate in the pathogenesis of neurodegenerative disorders.

“We have identified several new SMN candidate partners that function in RNA metabolism and translation. Notably, the FMRFM were of interest, and we showed that Rme signaling driven by PRMT1 regulates SMN-FMRP interactions,” the authors concluded. 

Reference

Binda O, Juillard F, Ducassou JN, et al. SMA-linked SMN mutants prevent phase separation properties and SMN interactions with FMRP family membersLife Sci Alliance. Published online November 14, 2022. doi:10.26508/lsa.202201429