Human tra2-beta1 autoregulates its protein concentration by influencing alternative splicing of its pre-mRNA
| Autor: | Oliver Nayler, Rosette Daoud, Stefan Stamm, Peter Stoilov |
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| Rok vydání: | 2004 |
| Předmět: |
Amino Acid Motifs
Blotting Western Exonic splicing enhancer Nerve Tissue Proteins Protein Serine-Threonine Kinases Biology Transfection Exon Protein splicing RNA Precursors Genetics Humans Phosphorylation Molecular Biology Genetics (clinical) DNA Primers Splice site mutation Serine-Arginine Splicing Factors Reverse Transcriptase Polymerase Chain Reaction Immune Sera Alternative splicing Intron RNA-Binding Proteins Exons General Medicine Protein-Tyrosine Kinases Molecular biology Cell biology Alternative Splicing Enhancer Elements Genetic Gene Expression Regulation Mutation RNA splicing Mutagenesis Site-Directed Precursor mRNA |
| Zdroj: | Human Molecular Genetics. 13:509-524 |
| ISSN: | 1460-2083 |
| DOI: | 10.1093/hmg/ddh051 |
| Popis: | HTRA2-BETA1 is an SR-like protein that regulates alternative splice site selection in a concentration-dependent manner. Its proper concentration is important as several pathological states are associated with its change. We investigated the mechanism that controls the cellular HTRA2-BETA1 concentration and found it utilizes a negative feedback loop to regulate the splicing of its exon 2. TRA2-BETA1 binds to four enhancers present in exon 2, which activates its inclusion. Inclusion of exon 2 generates mRNAs that are not translated into proteins. Mutations of exon 2 enhancers demonstrate that TRA2-BETA1 binds a degenerate sequence GHVVGANR, which is found more frequently in exons than in introns. Hyperphosphorylation of TRA2-BETA1 strongly reduces its binding to RNA. Presence of the CLK2 kinase prevents the usage of exons 2 and 3, generating the htra2-beta3 mRNA. The resulting HTRA2-BETA3 protein lacks the first RS domain of HTRA2-BETA1, is expressed in several tissues and has no influence on tra2-beta splice site selection. HTRA2-BETA1 interacting proteins promote exon 2 skipping by sequestering it, which upregulates the HTRA2-BETA1 protein synthesis. We propose that the regulation of the tra2-beta pre-mRNA alternative splicing provides a robust and sensitive molecular sensor that measures the ratio between HTRA2-BETA1 and its interacting proteins. |
| Databáze: | OpenAIRE |
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