Poly(A)-binding protein is an ataxin-2 chaperone that regulates biomolecular condensates

Structured and disordered regions of Ataxin-2 contribute differently to the specificity and efficiency of mRNP granule formation

“…Our observation that PABP co-immunoprecipitates with mini-Ataxin2, show that Atx2PAM2:PABP interactions occur independently of and prior to mRNP granule formation. Recent findings that this association antagonizes the Ataxin-2 condensation [82] are consistent with a model in which the Atx2-PAM2 motif interacts with PABP in translating mRNAs to support efficient translation. However, in addition to supporting translation, PABP is also known to associate with translational repressors that could drive either mRNA deadenylation and/or storage [93,108,109].…”

“…Given Ataxin-2’s therapeutic significance and multiple roles in biology, it is particularly important to determine which molecular activities of the protein are relevant to disease and to its various biological functions [ 81 ]. Across species, Ataxin-2 has three conserved regions: a Like-Sm (LSm) domain, an LSm-associated domain (LSm-AD) and a PAM2 motif, which is flanked by extended IDRs [ 82 ]. Detailed work in Drosophila has shown that a c-terminal IDR of Atx2 is selectively required for mRNP assembly into granules [ 61 ].…”

“…Parallel experiments showing that the IDR is also required for cytotoxicity in Drosophila FUS, C9ORF72 and Huntington’s disease models suggest RNP-granule formation to be a significant mechanism by which Atx2 promotes neurodegeneration [ 61 , 74 ]. A recent discovery that the Atx2-LSm domain antagonizes IDR-function has led to a model in which the Atx2 cIDR: (a) does not support mRNP assembly when Atx2 is associated with actively translating mRNAs through Atx2-LSm domain interactions; (b) becomes accessible and active in mediating mRNP assembly when LSm-domain interactions break and mRNA translation stalls [ 82 , 83 ].…”

Chaperone regulation of biomolecular condensates

“…While the chaperones discussed above are general protein chaperones or unfoldases, a number of studies have highlighted the unexpected chaperone activities of other condensate binding proteins such as nuclear/cytoplasmic transport machinery (Guo et al, 2018;Hofweber et al, 2018;Qamar et al, 2018;Yoshizawa et al, 2018;Guo et al, 2019;Bourgeois et al, 2020;Hutten et al, 2020;Niaki et al, 2020;Baade et al, 2021;Khalil et al, 2022;Odeh et al, 2022;Rhine et al, 2022;Boeynaems et al, 2023;Thomas et al, 2023). Many of the RNA-binding proteins whose aberrant condensation is associated with neurodegenerative diseases, including FUS, TDP-43 and hnRNPA1, are trafficked into the nucleus via importins like Karyopherin-β2 (Kapβ2 or transportin 1) and KPNB1.…”

“…In a different example of unexpected chaperoning activity, the stress granule marker Pab1 (or PABPC in humans) also serves as a chaperone to prevent spontaneous condensation of ataxin-2 and to direct its localization to stress granules during cellular stress (Boeynaems et al, 2023). PABPC binds to a conserved short linear motif (SLiM) in ataxin-2, and is proposed to function by bringing ataxin-2 to RNA, which then competes with the multivalent interactions that otherwise lead to spontaneous condensation.…”