Structural basis of human U5 snRNP late biogenesis and recycling

Pre-mRNA splicing by the spliceosome requires the biogenesis and recycling of its small nuclear ribonucleoprotein (snRNP) complexes, which are consumed in each round of splicing. The human U5 snRNP is the ~1 MDa ‘heart’ of the spliceosome and is recycled through an unknown mechanism involving major architectural rearrangements and the dedicated chaperones CD2BP2 and TSSC4. Late steps in U5 snRNP biogenesis similarly involve these chaperones. Here we report cryo-electron microscopy structures of four human U5 snRNP–CD2BP2–TSSC4 complexes, revealing how a series of molecular events primes the U5 snRNP to generate the ~2 MDa U4/U6.U5 tri-snRNP, the largest building block of the spliceosome. The biogenesis and recycling of the ‘heart’ of the human spliceosome, the U5 small nuclear ribonucleoprotein (snRNP), requires CD2BP2 and TSSC4. Here the authors present cryo-electron microscopy structures that reveal how these protein chaperones orchestrate the ATP-independent (re)generation of the U5 snRNP.