Mechanism of Phosphorylation-induced Activation of Phospholipase C-γ Isozymes*♦
| Autor: | Aurelie Gresset, T. Kendall Harden, Stephanie N. Hicks, John Sondek |
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| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Protein Conformation
Amino Acid Motifs Blotting Western Molecular Sequence Data Biology Phospholipase SH2 domain Biochemistry Isozyme src Homology Domains chemistry.chemical_compound Protein structure Animals Humans Amino Acid Sequence Phosphorylation Molecular Biology Cells Cultured Enzyme Assays Binding Sites Phospholipase C Sequence Homology Amino Acid Phospholipase C gamma Circular Dichroism Tyrosine phosphorylation Cell Biology Recombinant Proteins Rats Enzyme Activation HEK293 Cells chemistry Mutation Biophysics Enzymology Tyrosine Linker Protein Binding |
| Popis: | The lipase activity of most phospholipases C (PLCs) is basally repressed by a highly degenerate and mostly disordered X/Y linker inserted within the catalytic domain. Release of this auto-inhibition is driven by electrostatic repulsion between the plasma membrane and the electronegative X/Y linker. In contrast, PLC-γ isozymes (PLC-γ1 and -γ2) are structurally distinct from other PLCs because multiple domains are present in their X/Y linker. Moreover, although many tyrosine kinases directly phosphorylate PLC-γ isozymes to enhance their lipase activity, the underlying molecular mechanism of this activation remains unclear. Here we define the mechanism for the unique regulation of PLC-γ isozymes by their X/Y linker. Specifically, we identify the C-terminal SH2 domain within the X/Y linker as the critical determinant for auto-inhibition. Tyrosine phosphorylation of the X/Y linker mediates high affinity intramolecular interaction with the C-terminal SH2 domain that is coupled to a large conformational rearrangement and release of auto-inhibition. Consequently, PLC-γ isozymes link phosphorylation to phospholipase activation by elaborating upon primordial regulatory mechanisms found in other PLCs. |
| Databáze: | OpenAIRE |
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