Abstract
The spliceosome removes introns from precursor messenger RNA (pre-mRNA) to produce mature mRNA. Prior to catalysis, spliceosomes are assembled de novo onto pre-mRNA substrates. During this assembly process, U6 small nuclear RNA (snRNA) undergoes extensive structural remodeling. The early stages of this remodeling process are chaperoned by U6 snRNP proteins Prp24 and the Lsm2–8 heteroheptameric ring. We now report a structure of the U6 snRNP from Saccharomyces cerevisiae. The structure reveals protein–protein contacts that position Lsm2–8 in close proximity to the chaperone “active site” of Prp24. The structure also shows how the Lsm2–8 ring specifically recognizes U6 snRNA that has been post-transcriptionally modified at its 3′ end, thereby elucidating the mechanism by which U6 snRNPs selectively recruit 3′ end-processed U6 snRNA into spliceosomes. Additionally, the structure reveals unanticipated homology between the C-terminal regions of Lsm8 and the cytoplasmic Lsm1 protein involved in mRNA decay.
Highlights
The spliceosome removes introns from precursor messenger RNA to produce mature mRNA
U6 small nuclear RNA (snRNA) is unique among the spliceosomal RNAs in that its internal stem loop (ISL) must be transiently unwound and annealed to U4 snRNA during spliceosome assembly[11] by Prp[24], an RNA chaperone lacking homology to the ATP-dependent helicases
Prior crystal structures of S. cerevisiae Lsm[2,3,4,5,6,7,8] lacked the complete C-terminus of Lsm[8], which is known to control nuclear localization of the Lsm ring[36], and employed RNAs terminating with a 2′,3′-cis diol that do not resemble the modified form of U6 found in vivo[31,35,37,38]
Summary
The spliceosome removes introns from precursor messenger RNA (pre-mRNA) to produce mature mRNA. Spliceosomes are assembled de novo onto pre-mRNA substrates During this assembly process, U6 small nuclear RNA (snRNA) undergoes extensive structural remodeling. Eukaryotes are unique from bacteria and archaea in that they employ a massive and highly dynamic ribonucleoprotein assembly called the spliceosome to remove introns from precursor mRNA (pre-mRNA) before its translation into protein[1,2,3,4] This process likely arose to protect the transcriptome from invasive genetic elements[5], but evolved to expand the coding potential of the genome and afford layers of gene regulation that are a hallmark of eukaryotic life[6]. Prior crystal structures of S. cerevisiae Lsm[2,3,4,5,6,7,8] lacked the complete C-terminus of Lsm[8], which is known to control nuclear localization of the Lsm ring[36], and employed RNAs terminating with a 2′,3′-cis diol that do not resemble the modified form of U6 found in vivo[31,35,37,38]
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