Structural analysis of the lncRNA SChLAP1 reveals protein binding interfaces and a conformationally heterogenous retroviral insertion.

Abstract

The lncRNA Second Chromosome Locus Associated with Prostate 1 (SChLAP1) was previously identified as a predictive biomarker and potential driver of aggressive prostate cancer. Recent work suggested that SChLAP1 may bind the SWI/SNF chromatin remodeling complex to promote prostate cancer metastasis, though the exact role of SWI/SNF recognition is debated. To date, there are no detailed biochemical studies of apo SChLAP1 or SChLAP1:protein complexes. Herein, we report the first secondary structure model of SChLAP1 using SHAPE-MaP in vitro, in cellulo, and ex cellulo (protein-free). Comparison of the ex cellulo and in cellulo data via ΔSHAPE identified putative protein binding regions within SChLAP1. In addition, phylogenetic analysis revealed that SChLAP1 is a primate-conserved lncRNA, with two exons significantly derived from primate-specific retroviral insertions. In particular, we characterized a complex structural landscape in a protein binding region at the 3'end of SChLAP1 derived from a THE1B-type retroviral insertion, suggesting a role for an exapted RNA structure in SChLAP1:protein recognition and prostate cancer progression. Lastly, pulldowns of SChLAP1 substructures enabled identification of previously unestablished SChLAP1-interacting proteins. This work lays the foundation for future efforts to selectively target and disrupt SChLAP1 structures and/or protein interfaces and to develop new therapeutic avenues in prostate cancer treatment.