U2AF2 (U2AF Auxiliary Factor 2), also known as U2AF65, is a core spliceosomal protein essential for the recognition of the 3' splice site during pre-mRNA splicing. Located on chromosome 19q13.42, U2AF2 encodes a 475-amino acid protein that functions as the larger subunit of the U2AF heterodimer, with U2AF1 (U2AF35) serving as the smaller subunit. Together, these proteins recognize the polypyrimidine tract and the 3' splice site AG dinucleotide, facilitating the recruitment of the U2 small nuclear ribonucleoprotein (snRNP) to the branch point [@zhang1990].
U2AF2 plays a fundamental role in the spliceosome assembly cascade, one of the most complex and regulated processes in eukaryotic gene expression. The protein recognizes the consensus sequences at the 3' splice site and coordinates the sequential assembly of spliceosomal components. Beyond its canonical splicing function, U2AF2 has been implicated in various aspects of RNA metabolism, including mRNA transport, translation regulation, and RNA stability. These functions have made U2AF2 increasingly relevant to our understanding of neurodegenerative diseases, where RNA processing defects are recognized as central pathological mechanisms [@brooks2015].
Molecular Function and Mechanism
Role in Spliceosome Assembly
U2AF2 is a critical component of the early spliceosome assembly pathway:
Assembly Sequence:
E complex formation: U2AF2 (with U2AF1) binds the 3' splice site
A complex formation: U2 snRNP is recruited to the branch point
B complex formation: U4/U6.U5 tri-snRNP joins
Catalytic activation: Remodeling creates the active spliceosome
Splicing catalysis: Two transesterification reactions occur
Disassembly: snRNPs are recycled for new splicing events
Structural Features
The U2AF2 protein contains several functional domains:
N-terminal RS domain: Arginine-serine repeats for protein-protein interactions
RNA recognition motif (RRM) domains: Multiple RRMs for RNA binding
Polypyrimidine tract binding region: Specific recognition element
U2AF homology motif (UHM): Interfaces with U2AF1
RNA Binding Specificity
U2AF2 recognizes specific sequence elements:
Polypyrimidine tract: Stretch of 10-20 pyrimidines (U/C) preceding the splice site
3' AG dinucleotide: The absolutely conserved terminal nucleotides
Branch point recognition: Coordinates with branch point binding proteins
Exonic splicing enhancers (ESEs): Interacts with SR proteins
Interaction Network
U2AF2 interacts with multiple spliceosomal components:
U2AF1 (U2AF35): The heterodimer partner
U2AF1L4/L5: Related family members
SF3B complex: Core U2 snRNP component
SF1/BBP: Branch point binding protein
SR proteins: Serine/arginine-rich splicing factors
hnRNPs: Heterogeneous nuclear ribonucleoproteins
Disease Associations
Amyotrophic Lateral Sclerosis (ALS)
U2AF2 dysfunction is highly relevant to ALS pathogenesis:
Splicing Alterations:
SOD1 splicing defects: Altered exon skipping in ALS models
TDP-43 pathology: Affects U2AF2 function through aggregation