Structural Insights into Negative Cooperativity between Gemin2 and RNA in Sm-class snRNP Assembly

Abstract

Sm-class ribonucleoprotein particles (RNPs) are ring-shaped structures (Sm cores) formed by Sm hetero-heptamer around a segment of RNA, containing a nonameric oligoribonucleotide, PuAUUUNUGPu, followed by a stem-loop, and are basic structural modules critical for stability and functions of spliceosomal, telomerase and U7 RNPs. In the chaperones-assisted Sm core assembly, Gemin2 of the SMN complex, not only binds SmD1/D2/F/E/G (5Sm), but also serves as a checkpoint via a negative cooperativity mechanism uncovered in our recent study: Gemin2 constricts the horseshoe-shaped 5Sm in a narrow conformation from outside, preventing non-cognate RNA and SmD3/B from joining; only cognate RNA can bind inside 5Sm and widen 5Sm, dissociating Gemin2 from 5Sm and recruiting SmD3/B. However, the structural mechanics is unknown. Here I describe a coordinate-improved structure of 5Sm bound by Gemin2/SMN. Moreover, via new analysis, comparison of this structure with those of newly coordinate-improved Sm cores reveals the negative cooperativity mechanism between Gemin2 and RNA in binding 5Sm at atomic resolution level and provides structural insights into RNA selection and Gemin2s release in Sm core assembly. Finally, implications in the evolution of the Sm-core assembly chaperoning machinery and the neurodegenerative disease spinal muscular atrophy caused by SMN deficiency are discussed.