title: Fetal Alz-50 clone 1 interacts with the human orthologue of the Kelch-like Ech-associated protein.
abstract: The fetal Alz-50 reactive clone 1 (FAC1) protein exhibits altered expression and subcellular localization during neuronal development and neurodegenerative diseases such as Alzheimer's disease. Using the yeast two-hybrid screen, the human orthologue of Keap1 (hKeap1) was identified as a FAC1 interacting protein. Keap1 is an important regulator of the oxidative stress response pathway through its interaction with the Nrf family of transcription factors. An interaction between full-length FAC1 and hKeap1 proteins has been demonstrated, and the FAC1 binding domain of hKeap1 has been identified as the Kelch repeats. In addition, FAC1 colocalizes with endogenous Keap1 within the cytoplasm of PT67 cells. Exogenously introduced eGFP:hKeap1 fusion protein redistributed FAC1 to colocalize with eGFP:hKeap1 in perinuclear, spherical structures. The interaction between FAC1 and hKeap1 is reduced by competition with the Nrf2 protein. However, competition by Nrf2 for hKeap1 is reduced by diethylmaleate (DEM), a known disrupter of the Nrf2:Keap1 interaction. DEM does not affect the ability of FAC1 to bind hKeap1 in our assay. These results suggest that hKeap1 regulates FAC1 in addition to its known role in control of Nrf2. Furthermore, the observed competition between FAC1 and Nrf2 for binding hKeap1 indicates that the interplay between these three proteins has important implications for neuronal response to oxidative stress.
authors.affiliation: Department of Pathology, University of Pennsylvania, 4010 Locust Street, Philadelphia, Pennsylvania 19104-6030, USA.
authors.forename: Gordon D
authors.initials: GD
authors.lastname: Strachan
authors.forename: Kathleen L
authors.initials: KL
authors.lastname: Morgan
authors.forename: Linda L
authors.initials: LL
authors.lastname: Otis
authors.forename: John
authors.initials: J
authors.lastname: Caltagarone
authors.forename: Aryn
authors.initials: A
authors.lastname: Gittis
authors.forename: Robert
authors.initials: R
authors.lastname: Bowser
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Jordan-Sciutto
mesh_terms: D000199:Actins / Q000378:metabolism; D020816:Amino Acid Motifs; D000818:Animals; D034961:Antigens, Nuclear; D001667:Binding, Competitive / Q000187:drug effects; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000494:pharmacology; D005347:Fibroblasts; D005786:Gene Expression Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D000072019:Kelch-Like ECH-Associated Protein 1; D008298:Maleates / Q000494:pharmacology; D051379:Mice; D051267:NF-E2-Related Factor 2; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism / Q000494:pharmacology; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D000092468:Bromodomain Containing Proteins
chemical_list: D000199:Actins; D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D000072019:Kelch-Like ECH-Associated Protein 1; D008298:Maleates; D051267:NF-E2-Related Factor 2; D009419:Nerve Tissue Proteins; D011506:Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C431364:KEAP1 protein, human; C495635:NFE2L2 protein, human; C495636:Nfe2l2 protein, mouse; C406238:fetal Alzheimer antigen; D000092468:Bromodomain Containing Proteins; C014476:diethyl maleate