NDLI: Galectin-1 dimers can scaffold Raf-effectors to increase H-ras nanoclustering

Content Provider	PubMed Central
Author	Olga, Blaževitš Mideksa, Yonatan G. Šolman, Maja Ligabue, Alessio Ariotti, Nicholas Hossein, Nakhaeizadeh Fansa, Eyad K. Papageorgiou, Anastassios C. Alfred, Wittinghofer Ahmadian, Md. R. Daniel, Abankwa
Copyright Year	2016
Abstract	Galectin-1 (Gal-1) dimers crosslink carbohydrates on cell surface receptors. Carbohydrate-derived inhibitors have been developed for cancer treatment. Intracellularly, Gal-1 was suggested to interact with the farnesylated C-terminus of Ras thus specifically stabilizing GTP-H-ras nanoscale signalling hubs in the membrane, termed nanoclusters. The latter activity may present an alternative mechanism for how overexpressed Gal-1 stimulates tumourigenesis. Here we revise the current model for the interaction of Gal-1 with H-ras. We show that it indirectly forms a complex with GTP-H-ras via a high-affinity interaction with the Ras binding domain (RBD) of Ras effectors. A computationally generated model of the Gal-1/C-Raf-RBD complex is validated by mutational analysis. Both cellular FRET as well as proximity ligation assay experiments confirm interaction of Gal-1 with Raf proteins in mammalian cells. Consistently, interference with H-rasG12V-effector interactions basically abolishes H-ras nanoclustering. In addition, an intact dimer interface of Gal-1 is required for it to positively regulate H-rasG12V nanoclustering, but negatively K-rasG12V nanoclustering. Our findings suggest stacked dimers of H-ras, Raf and Gal-1 as building blocks of GTP-H-ras-nanocluster at high Gal-1 levels. Based on our results the Gal-1/effector interface represents a potential drug target site in diseases with aberrant Ras signalling.
Related Links	http://dx.doi.org/10.1038/srep24165
Starting Page	24165
File Format	PDF
ISSN	20452322
e-ISSN	20452322
Journal	Scientific Reports
Volume Number	6
Language	English
Publisher	Nature Publishing Group
Publisher Date	2016-04-01
Access Restriction	Open
Rights Holder	Nature Publishing Group
Subject Keyword	Science and technology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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Galectin-1 dimers can scaffold Raf-effectors to increase H-ras nanoclustering

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

K-Ras Nanoclustering is Subverted by Over-expression of the Scaffold Protein Galectin-3

The Efficacy of Raf Kinase Recruitment to the GTPase H-ras Depends on H-ras Membrane Conformer-specific Nanoclustering* ♦

Conformation of the GTPase Ras in the Membrane Affects Nanoscale Clustering and Raf Kinase Recruitment♦ The Efficacy of Raf Kinase Recruitment to the GTPase H-ras Depends on H-ras Membrane Conformer-specific Nanoclustering

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Galectin-1 dimers can scaffold Raf-effectors to increase H-ras nanoclustering

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Galectin-1 dimers can scaffold Raf-effectors to increase H-ras nanoclustering

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