title: Identification and analysis of a novel dimerization domain shared by various members of c-Jun N-terminal kinase (JNK) scaffold proteins.
abstract: Mitogen-activated protein kinases (MAPKs) form a kinase tier module in which MAPK, MAP2K, and MAP3K are held by scaffold proteins. The scaffold proteins serve as a protein platform for selective and spatial kinase activation. The precise mechanism by which the scaffold proteins function has not yet been fully explained. WDR62 is a novel scaffold protein of the c-Jun N-terminal kinase (JNK) pathway. Recessive mutations within WDR62 result in severe cerebral cortical malformations. One of the WDR62 mutant proteins found in a patient with microcephaly encodes a C-terminal truncated protein that fails to associate efficiently with JNK and MKK7β1. The present article shows that the WDR62 C-terminal region harbors a novel dimerization domain composed of a putative loop-helix domain that is necessary and sufficient for WDR62 dimerization and is critical for its scaffolding function. The loop-helix domain is highly conserved between orthologues and is also shared by the JNK scaffold protein, JNKBP1/MAPKBP1. Based on the high sequence conservation of the loop-helix domain, our article shows that MAPKBP1 homodimerizes and heterodimerizes with WDR62. Endogenous WDR62 and MAPKBP1 co-localize to stress granules following arsenite treatment, but not during mitosis. This study proposes another layer of complexity, in which coordinated activation of signaling pathways is mediated by the association between the different JNK scaffold proteins depending on their biological function.
authors: Department of Molecular Genetics, The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa 31096, Israel.
authors: Ksenya
authors: K
authors: Cohen-Katsenelson
authors: Tanya
authors: T
authors: Wasserman
authors: Ilona
authors: I
authors: Darlyuk-Saadon
authors: Alona
authors: A
authors: Rabner
authors: Fabian
authors: F
authors: Glaser
authors: Ami
authors: A
authors: Aronheim
mesh_terms: D000595:Amino Acid Sequence; D018053:Arsenites / Q000494:pharmacology; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D018797:Cell Cycle Proteins; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D048688:MAP Kinase Kinase 7 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018613:Microscopy, Confocal; D048056:Mitogen-Activated Protein Kinase 9 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D017386:Sequence Homology, Amino Acid
chemical_list: D018053:Arsenites; D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; C580778:MAPKBP1 protein, human; D009419:Nerve Tissue Proteins; C552527:WDR62 protein, human; D048056:Mitogen-Activated Protein Kinase 9; D048688:MAP Kinase Kinase 7; C482569:MAP2K7 protein, human; C015001:arsenite