Abstract
U1 snRNP plays a critical role in 5ʹ-splice site recognition and is a frequent target of alternative splicing factors. These factors transiently associate with human U1 snRNP and are not amenable for structural studies, while their Saccharomyces cerevisiae (yeast) homologs are stable components of U1 snRNP. Here, we report the cryoEM structure of yeast U1 snRNP at 3.6 Å resolution with atomic models for ten core proteins, nearly all essential domains of its RNA, and five stably associated auxiliary proteins. The foot-shaped yeast U1 snRNP contains a core in the “ball-and-toes” region architecturally similar to the human U1 snRNP. All auxiliary proteins are in the “arch-and-heel” region and connected to the core through the Prp42/Prp39 paralogs. Our demonstration that homodimeric human PrpF39 directly interacts with U1C-CTD, mirroring yeast Prp42/Prp39, supports yeast U1 snRNP as a model for understanding how transiently associated auxiliary proteins recruit human U1 snRNP in alternative splicing.
Highlights
U1 small nuclear ribonucleoprotein complexes (snRNPs) plays a critical role in 5ʹ-splice site recognition and is a frequent target of alternative splicing factors
Our demonstration that homodimeric human PrpF39 directly interacts with U1C-C-terminal domain (CTD), mirroring yeast Prp42/Prp[39], supports yeast U1 snRNP as a model for understanding how transiently associated auxiliary proteins recruit human U1 snRNP in alternative splicing
The modeled yeast U1 snRNP has a dimension of ~200 × 120 × 80 Å with the overall shape resembling a foot in three dimensions (Fig. 1d)
Summary
U1 snRNP plays a critical role in 5ʹ-splice site recognition and is a frequent target of alternative splicing factors. These factors transiently associate with human U1 snRNP and are not amenable for structural studies, while their Saccharomyces cerevisiae (yeast) homologs are stable components of U1 snRNP. Several partial structures of human U1 snRNP either reconstituted from individual components or obtained from limited proteolysis of U1 snRNP purified from HeLa cells have been determined with X-ray crystallography[8,9,10] The combination of these structures reveals the protein–protein and protein–RNA interaction networks in human U1 snRNP, as well as the structural basis of 5ʹ-ss recognition. This structure provides a framework to integrate a wealth of existing genetic and biochemical data on yeast U1 snRNP as well as to understand the structure and function of human auxiliary a MW (kDa)
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