3NKX

Impaired binding of 14-3-3 to Raf1 is linked to Noonan and LEOPARD syndrome

Summary for 3NKX

• Entry DOI: 10.2210/pdb3nkx/pdb
• Related: 2o02 2o98 3e6y 3lw1 3m50 3m51
• Descriptor: 14-3-3 protein zeta/delta, Peptide of RAF proto-oncogene serine/threonine-protein kinase, PROPANOIC ACID, ... (4 entities in total)
• Functional Keywords: protein binding, signaling protein
• Biological source: Homo sapiens (human); More
• Cellular location: Cytoplasm : P63104 P04049
• Total number of polymer chains: 4
• Total formula weight: 58044.61

Authors

Schumacher, B.,Weyand, M.,Ottmann, C. (deposition date: 2010-06-21, release date: 2010-09-15, Last modification date: 2024-10-30)

Primary citation

Molzan, M.,Schumacher, B.,Ottmann, C.,Baljuls, A.,Polzien, L.,Weyand, M.,Thiel, P.,Rose, R.,Rose, M.,Kuhenne, P.,Kaiser, M.,Rapp, U.R.,Kuhlmann, J.,Ottmann, C.
Impaired binding of 14-3-3 to C-RAF in Noonan syndrome suggests new approaches in diseases with increased Ras signaling
Mol.Cell.Biol., 30:4698-4711, 2010

PubMed Abstract: The Ras-RAF-mitogen-activated protein kinase (Ras-RAF-MAPK) pathway is overactive in many cancers and in some developmental disorders. In one of those disorders, namely, Noonan syndrome, nine activating C-RAF mutations cluster around Ser(259), a regulatory site for inhibition by 14-3-3 proteins. We show that these mutations impair binding of 14-3-3 proteins to C-RAF and alter its subcellular localization by promoting Ras-mediated plasma membrane recruitment of C-RAF. By presenting biophysical binding data, the 14-3-3/C-RAFpS(259) crystal structure, and cellular analyses, we indicate a mechanistic link between a well-described human developmental disorder and the impairment of a 14-3-3/target protein interaction. As a broader implication of these findings, modulating the C-RAFSer(259)/14-3-3 protein-protein interaction with a stabilizing small molecule may yield a novel potential approach for treatment of diseases resulting from an overactive Ras-RAF-MAPK pathway.

PubMed: 20679480
DOI: 10.1128/MCB.01636-09

Experimental method

X-RAY DIFFRACTION (2.4 Å)