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Abstract
Sam68 and T-STAR are members of the STAR family of proteins that directly link signal transduction with post-transcriptional gene regulation. Sam68 controls the alternative splicing of many oncogenic proteins. T-STAR is a tissue-specific paralogue that regulates the alternative splicing of neuronal pre-mRNAs. STAR proteins differ from most splicing factors, in that they contain a single RNA-binding domain. Their specificity of RNA recognition is thought to arise from their property to homodimerize, but how dimerization influences their function remains unknown. Here, we establish at atomic resolution how T-STAR and Sam68 bind to RNA, revealing an unexpected mode of dimerization different from other members of the STAR family. We further demonstrate that this unique dimerization interface is crucial for their biological activity in splicing regulation, and suggest that the increased RNA affinity through dimer formation is a crucial parameter enabling these proteins to select their functional targets within the transcriptome.
Highlights
Sam[68] and T-STAR are members of the STAR family of proteins that directly link signal transduction with post-transcriptional gene regulation
Sam[68] is phosphorylated by tyrosine kinases such as Src[1,2] and serine/threonine kinases such as extracellular signal-regulated kinase 1 (Erk1) and cyclin-dependent kinase 1 (Cdk1), arginine methylated by protein arginine methyltransferase 1 (PRMT1), lysine acetylated by CREB-binding protein (CBP)[9] and sumoylated[10], and most of these modifications affect the functions of Sam[68] in RNA metabolism, including its RNAbinding ability[9,11,12,13], nuclear localization[8] and effects on alternative splicing[6,14]
Our data indicate that these proteins function in splicing control as dimers, and this dimerization is mediated by a novel interface not found in the more distantly related STAR proteins quaking, GLD-1 and splicing factor 1 (SF1)
Summary
Sam[68] and T-STAR are members of the STAR family of proteins that directly link signal transduction with post-transcriptional gene regulation. T-STAR is a tissue-specific paralogue that regulates the alternative splicing of neuronal pre-mRNAs. STAR proteins differ from most splicing factors, in that they contain a single RNA-binding domain. STAR proteins differ from most splicing factors, in that they contain a single RNA-binding domain Their specificity of RNA recognition is thought to arise from their property to homodimerize, but how dimerization influences their function remains unknown. The first group comprises the proteins SF1, QKI and GLD-1, which bind RNA motifs with a common (U/C)ACU(C/A)A(C/U) consensus sequence[33,34,35] Structural studies of these proteins revealed that the QUA1 region is responsible for dimerization of the STAR domain[36,37], while the KH domains recognize the 30 U(C/A)A(C/U) moiety of the RNA. Structural studies have shown that the QUA1 domain plays a role in dimerization[43], but the structural basis of RNA recognition and the mechanisms of action of the Sam68/T-STAR group of proteins in RNA metabolism remain unknown
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