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SR protein

SR , or serine/arginine-rich proteins, are a family of essential splicing factors that play a crucial role in the regulation of alternative splicing—a process vital for the diversity and complexity of eukaryotic proteomes. The intricate dance of splicing, the removal of non-coding introns and joining of coding exons, is orchestrated by a complex machinery, where SR proteins emerge as key choreographers.

The term “SR ” originates from the presence of serine (S) and arginine (R) residues within their sequences. These proteins typically possess one or more recognition motifs (RRMs) and a domain rich in serine and arginine. Their unique composition allows SR proteins to engage in dynamic interactions with RNA , particularly during the spliceosome assembly and splicing process.

Alternative splicing is a sophisticated mechanism that enables the generation of multiple mRNA transcripts from a single gene, expanding the coding capacity of the genome. This process is pivotal for the production of diverse protein isoforms with distinct functions, often tissue-specific or developmentally regulated. SR proteins act as crucial regulators of alternative splicing by binding to specific RNA sequences and influencing splice site selection.

The hallmark feature of SR proteins is their ability to modulate splice site selection through interactions with exonic and intronic splicing enhancer elements. Exonic splicing enhancers (ESEs) are short RNA sequences within exons that promote the recruitment of the splicing machinery, while intronic splicing enhancers (ISEs) are found in introns and also facilitate spliceosome assembly. SR proteins bind to these enhancer elements, promoting the inclusion of adjacent exons in the mature mRNA.

The dynamic nature of SR protein activity is exemplified by their phosphorylation. Phosphorylation, a reversible modification of proteins, is a key regulatory mechanism in . SR proteins undergo phosphorylation by serine/arginine-rich protein kinases (SRPKs) and cyclin-dependent kinases (CDKs), leading to changes in their conformation and activity. Phosphorylated SR proteins exhibit enhanced binding affinity for RNA, promoting spliceosome assembly and alternative splicing.

The interplay between SR proteins and the spliceosome, a complex molecular machine responsible for splicing, is intricate and finely regulated. SR proteins participate in spliceosome assembly by interacting with components of the U1 small nuclear ribonucleoprotein (snRNP), a key player in recognizing the 5′ splice site. Additionally, they collaborate with U2 auxiliary factor (U2AF) to promote the recognition of the 3′ splice site.

One of the well-studied members of the SR protein family is SRSF1, also known as ASF/SF2 (alternative splicing factor/splicing factor 2). SRSF1 is involved in diverse cellular processes, including apoptosis and mRNA export. Dysregulation of SRSF1 has been implicated in various diseases, including , highlighting the importance of SR proteins in maintaining .

Beyond their role in alternative splicing, SR proteins have been implicated in other cellular processes. They contribute to mRNA export from the nucleus to the cytoplasm by interacting with components of the nuclear pore complex. Additionally, SR proteins play a role in mRNA translation, influencing the efficiency of .

The significance of SR proteins extends to the field of human genetics and disease. Mutations in genes encoding SR proteins have been associated with neurodevelopmental disorders and various cancers. Altered splicing patterns, resulting from dysregulated SR protein activity, can lead to aberrant expression of protein isoforms with implications for and disease progression.

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