3O8I

Structure of 14-3-3 isoform sigma in complex with a C-Raf1 peptide and a stabilizing small molecule fragment

Summary for 3O8I

• Entry DOI: 10.2210/pdb3o8i/pdb
• Related: 1YWT 1YZ5 3CU8 3LW1
• Descriptor: 14-3-3 protein sigma, 14-3-3 binding site peptide of RAF proto-oncogene serine/threonine-protein kinase, 6,6-dihydroxy-1-methoxyhexan-2-one, ... (4 entities in total)
• Functional Keywords: protein-protein complex, 14-3-3, protein-protein interaction, phosphorylation, peptide binding protein
• Biological source: Homo sapiens (human); More
• Cellular location: Cytoplasm: P31947; Cytoplasm (By similarity): P04049
• Total number of polymer chains: 2
• Total formula weight: 28188.60

Authors

Ottmann, C.,Rose, R.,Kaiser, M.,Kuhenne, P. (deposition date: 2010-08-03, release date: 2010-09-29, Last modification date: 2024-10-16)

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 Å)