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Probing Gαi1 protein activation at single-amino acid resolution.

  • Sun D Laboratory of Biomolecular Research, Paul Scherrer Institute, Villigen, Switzerland.
  • Flock T Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom.
  • Deupi X Laboratory of Biomolecular Research, Paul Scherrer Institute, Villigen, Switzerland.
  • Maeda S Laboratory of Biomolecular Research, Paul Scherrer Institute, Villigen, Switzerland.
  • Matkovic M Laboratory of Biomolecular Research, Paul Scherrer Institute, Villigen, Switzerland.
  • Mendieta S Laboratory of Biomolecular Research, Paul Scherrer Institute, Villigen, Switzerland.
  • Mayer D Laboratory of Biomolecular Research, Paul Scherrer Institute, Villigen, Switzerland.
  • Dawson R F. Hoffmann-La Roche AG, Pharma Research & Early Development, Discovery Technologies, Basel, Switzerland.
  • Schertler GFX Laboratory of Biomolecular Research, Paul Scherrer Institute, Villigen, Switzerland.
  • Madan Babu M Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom.
  • Veprintsev DB Laboratory of Biomolecular Research, Paul Scherrer Institute, Villigen, Switzerland.
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  • 2015-08-11
Published in:
  • Nature structural & molecular biology. - 2015
Amino Acids
DNA
DNA Mutational Analysis
GTP-Binding Protein alpha Subunits
Humans
Models, Molecular
Protein Binding
Protein Conformation
Protein Stability
Rhodopsin
English We present comprehensive maps at single-amino acid resolution of the residues stabilizing the human Gαi1 subunit in nucleotide- and receptor-bound states. We generated these maps by measuring the effects of alanine mutations on the stability of Gαi1 and the rhodopsin-Gαi1 complex. We identified stabilization clusters in the GTPase and helical domains responsible for structural integrity and the conformational changes associated with activation. In activation cluster I, helices α1 and α5 pack against strands β1-β3 to stabilize the nucleotide-bound states. In the receptor-bound state, these interactions are replaced by interactions between α5 and strands β4-β6. Key residues in this cluster are Y320, which is crucial for the stabilization of the receptor-bound state, and F336, which stabilizes nucleotide-bound states. Destabilization of helix α1, caused by rearrangement of this activation cluster, leads to the weakening of the interdomain interface and release of GDP.
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  • English
Open access status
green
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https://sonar.ch/global/documents/278294
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