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  The efficacy of Raf kinase recruitment to the GTPase H-ras depends on H-ras membrane conformer-specific nanoclustering.

Guzmán, C., Solman, M., Ligabue, A., Blasevits, O., Andrade, D., Reymond, L., et al. (2014). The efficacy of Raf kinase recruitment to the GTPase H-ras depends on H-ras membrane conformer-specific nanoclustering. The Journal of Biological Chemistry, 289, 9519-9533. doi:10.1074/jbc.M113.537001.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0019-8B44-B Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0027-CF1E-A
Genre: Journal Article

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Guzmán, C. , Author
Solman, M., Author
Ligabue, A., Author
Blasevits, O., Author
Andrade, D.1, Author              
Reymond, L., Author
Eggeling, C.1, Author              
Affiliations:
1Department of NanoBiophotonics, MPI for biophysical chemistry, Max Planck Society, ou_578627              

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 Abstract: Solution structures and biochemical data have provided a wealth of mechanistic insight into Ras GTPases. However, information on how much the membrane organization of these lipid-modified proteins impacts on their signaling is still scarce. Ras proteins are organized into membrane nanoclusters, which are necessary for Ras-MAPK signaling. Using quantitative conventional and super-resolution fluorescence methods, as well as mathematical modeling, we investigated nanoclustering of H-ras helix α4 and hypervariable region mutants that have different bona fide conformations on the membrane. By following the emergence of conformer-specific nanoclusters in the plasma membrane of mammalian cells, we found that conformers impart distinct nanoclustering responses depending on the cytoplasmic levels of the nanocluster scaffold galectin-1. Computational modeling revealed that complexes containing H-ras conformers and galectin-1 affect both the number and lifetime of nanoclusters and thus determine the specific Raf effector recruitment. Our results show that mutations in Ras can affect its nanoclustering response and thus allosterically effector recruitment and downstream signaling. We postulate that cancer- and developmental disease-linked mutations that are associated with the Ras membrane conformation may exhibit so far unrecognized Ras nanoclustering and therefore signaling alterations.

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Language(s): eng - English
 Dates: 2014-02-252014-04-04
 Publication Status: Published in print
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 Rev. Method: Peer
 Identifiers: DOI: 10.1074/jbc.M113.537001
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Title: The Journal of Biological Chemistry
Source Genre: Journal
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Pages: - Volume / Issue: 289 Sequence Number: - Start / End Page: 9519 - 9533 Identifier: -