Grb2 Y160F mutant mimics the wild-type monomeric state dynamics and the monomer-dimer equilibrium
The Growth factor receptor-bound protein 2 (Grb2) participates in early signaling complexes and regulates tyrosine kinase-mediated signal transduction through a monomer-dimer equilibrium. Grb2 dimeric state inhibits signal transduction whereas the monomer promotes signaling downstream. Since Grb2 di...
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| Published in: | International journal of biological macromolecules Vol. 279; no. Pt 1; p. 134945 |
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| Main Authors: | , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
Netherlands
Elsevier B.V
01-11-2024
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| Subjects: | |
| Online Access: | Get full text |
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| Summary: | The Growth factor receptor-bound protein 2 (Grb2) participates in early signaling complexes and regulates tyrosine kinase-mediated signal transduction through a monomer-dimer equilibrium. Grb2 dimeric state inhibits signal transduction whereas the monomer promotes signaling downstream. Since Grb2 dimer KD is ∼0.8 μM, studies focused on the monomer are still challenging and require mutations or interaction with phosphotyrosine peptides. However, these mutants were never characterized considering their effects on protein structure and dynamics in solution. Here, we present the biophysical characterization of Grb2Y160F, the first Grb2 mutant to induce protein monomerization without disrupting its native behavior in solution due to net charge modifications or interaction with peptides. We also identified that Grb2Y160F exists in a monomer-dimer equilibrium. Grb2Y160F ability to dimerize implies that different dimerization interfaces might regulate signaling pathways in distinct ways and raises an important question about the role of the Y160 residue in other dimerization interfaces.
•Grb2 is predominantly found in its auto-inhibited form (dimer) in solution.•Grb2 Y160F exhibits a monomer-dimer equilibrium that favors the monomer in solution.•Grb2 Y160F presents a slingshot like mechanism that induces dimer dissociation.•SAXS and MD were combined to determine the Grb2 Y160F monomer ensemble in solution.•The ability of Grb2 Y160F to dimerize suggests distinct dimerization interfaces. |
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| Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
| ISSN: | 0141-8130 1879-0003 1879-0003 |
| DOI: | 10.1016/j.ijbiomac.2024.134945 |