Atomic-scale structural insights into the functional roles of the full low complexity domain of the hnRNPA1 protein

Abstract

AbstracthnRNPA1, a protein from the heterogeneous-nuclear ribonucleoprotein family, mediates cellular processes such as RNA metabolism and DNA telomere maintenance. Besides the folded RNA recognition motifs, hnRNPA1 has a ∼ 135 amino-acids long low-complexity domain (LCD) consisting of RGG-repeats region and a prion-like domain (PrLD). Biochemical data suggest that RGG-rich region modulates recognition of telomeric repeats, while PrLD is often implicated in formation of biomolecular condensates. Here, we utilize recent experimental data from techniques like NMR, DEER and SAXS on hnRNPA1-LCD and integrated that with ∼ 100 µ-seconds molecular simulations trajectory data to elucidate the Boltzmann-weighted atomic-resolution conformational ensemble of hnRNP1-LCD and study its interaction with telomeric G-quadruplexes (GQs). Single chain statistics and abundance of molecular motifs as well as consistency with low-resolution experimentally reported structural data suggest faithful recapitulation of local interactions. We observe multi-domain structural architecture for the LCD suggesting that functional modularity may be encoded in very long IDPs. Our binding simulations studies reveal that some conformations from RGG-rich region destabilize telomeric GQ, which may be an important first step in unfolding activities at the telomeric end. Spontaneous appearances of kinked beta sheet motifs within the hnRNPA1-LCD hint at possible nucleation centres of reversible biomolecular condensate formation.