# Understanding the structure and function of U1 snRNP

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2021 · $451,670

## Abstract

Abstract
Pre-mRNA splicing is essential for gene expression in all eukaryotes and errors in splicing cause genetic
disorders and many other diseases. A thorough understanding of the molecular mechanisms of pre-mRNA
splicing has the potential to provide useful approaches for human disease therapy. The splicing of introns is
carried out through two transesterification reactions catalyzed by the spliceosome, a large RNA/protein
complex composed of five snRNPs (U1, U2, U4, U5, U6) and many non-snRNP related protein factors. Despite
the recent determination of multiple high resolution cryo EM structures of spliceosome complexes at later
stages of the splicing pathway, there is a lack of structural and mechanistic understanding of the initial intron
recognition and early spliceosome assembly events.
U1 snRNP is critical for the initial recognition of 5' splice site (ss). Due to its important role in 5' ss recognition,
U1 snRNP is a frequent target of the action of alternative splicing factors that either facilitate or prevent U1
snRNP from binding to 5' ss. Much of what we know today about the molecular mechanism and regulation of 5'
ss recognition comes from genetic, biochemical, and structural studies of two commonly used model systems,
S. cerevisiae (yeast) and human U1 snRNP. Intriguingly, the yeast U1 snRNP is much more complex than the
human U1 snRNP. Yeast U1 snRNA contains a 3.5-fold larger RNA and seven additional proteins, most of
which have human homologs that are weakly associated with U1 snRNP and are involved in alternative
splicing. We have recently determined the cryoEM structure of yeast U1 snRNP to 3.6 Å resolution, generating
many interesting hypotheses on how human alternative splicing factors recruit U1 snRNP and the unexpected
role of human PrpF39 in alternative splicing. We will test these hypotheses using a combination of
biochemistry and molecular biology approaches. We will also decipher the molecular mechanism of concerted
recognition of all intron elements through a combination of structural biology and biochemical approaches.
Results from this project will significantly advance our understanding of the molecular mechanism of intron
definition and alternative splicing.

## Key facts

- **NIH application ID:** 10200085
- **Project number:** 5R01GM126157-04
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** RUI ZHAO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $451,670
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10200085

## Citation

> US National Institutes of Health, RePORTER application 10200085, Understanding the structure and function of U1 snRNP (5R01GM126157-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10200085. Licensed CC0.

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