Functional and Crystal Structure Analysis of Active Site Adaptations of a Potent Anti-Angiogenic Human tRNA Synthetase
| Autor: | Min Guo, Xiang-Lei Yang, Francella J. Otero, Karla L. Ewalt, Duncan E. McRee, Mili Kapoor, Robert J. Skene, Paul Schimmel |
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| Rok vydání: | 2007 |
| Předmět: |
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Molecular Protein Folding RNA Splicing Molecular Sequence Data Aminoacylation Angiogenesis Inhibitors Tryptophan-tRNA Ligase Tryptophan—tRNA ligase Biology Crystallography X-Ray Article Substrate Specificity Geobacillus stearothermophilus Protein structure Bacterial Proteins Structural Biology Humans Amino Acid Sequence Binding site Molecular Biology chemistry.chemical_classification DNA ligase Binding Sites Active site Acetylation Protein Structure Tertiary chemistry Biochemistry Transfer RNA Mutation biology.protein RNA Protein folding |
| Zdroj: | Structure. 15(7):793-805 |
| ISSN: | 0969-2126 |
| DOI: | 10.1016/j.str.2007.05.009 |
| Popis: | Higher eukaryote tRNA synthetases have expanded functions with roles in the assembly of biological systems. New functions come from enlarged, more differentiated structures that were adapted to fit with the essential aminoacylation function. How those adaptations affect catalytic mechanism is not known. Presented here is the structure of a catalytically active natural splice variant of human tryptophanyl-tRNA synthetase that is a potent angiostatic factor. This and related structures suggest a eukaryote-specific N-terminal extension of the core enzyme changed substrate recognition by forming an active site ‘cap’. And, at the junction of the extension and core catalytic unit, an arginine is recruited to replace a missing ‘landmark’ lysine that is almost 200 amino acids down the sequence. Mutagenesis, rapid kinetic, and substrate binding studies support the functional significance of the cap and of the arginine recruitment. Thus, the enzyme function of human TrpRS has switched more to the N-terminus of the sequence. This switch has the effect of creating selective pressure to retain the N-terminal extension for functional expansion. |
| Databáze: | OpenAIRE |
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