Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 22, Issue 9, Pages 686-U64Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.3070
Keywords
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Funding
- Roche [RPF113]
- Boehringer Ingelheim Fonds
- Paul Scherrer Institute
- Swiss National Science Foundation [141898, 133810 31-135754, 31-153145, 31003A-146520]
- Swiss National Centre of Competence in Research (NCCR) Structural Biology
- NCCR Molecular Systems Engineering
- European Cooperation in Science and Technology [CM1207]
- Marie Curie Initial Training Network NanoMem
- Medical Research Council [MC_U105185859]
- Lister Institute Research
- Swiss National Science Foundation (SNF) [31003A_146520] Funding Source: Swiss National Science Foundation (SNF)
- MRC [MC_U105185859] Funding Source: UKRI
- Medical Research Council [MC_U105185859, 1274107] Funding Source: researchfish
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We present comprehensive maps at single-amino acid resolution of the residues stabilizing the human G alpha(i1) subunit in nucleotide- and receptor-bound states. We generated these maps by measuring the effects of alanine mutations on the stability of G alpha(i1) and the rhodopsin-G alpha(i1) 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 alpha 1 and alpha 5 pack against strands beta 1-beta 3 to stabilize the nucleotide-bound states. In the receptor-bound state, these interactions are replaced by interactions between alpha 5 and strands beta 4-beta 6. 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 alpha 1, caused by rearrangement of this activation cluster, leads to the weakening of the interdomain interface and release of GDP.
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