title: Structural and molecular characterization of iron-sensing hemerythrin-like domain within F-box and leucine-rich repeat protein 5 (FBXL5).
abstract: Mammalian cells maintain iron homeostasis by sensing changes in bioavailable iron levels and promoting adaptive responses. FBXL5 is a subunit of an E3 ubiquitin ligase complex that mediates the stability of iron regulatory protein 2, an important posttranscriptional regulator of several genes involved in iron metabolism. The stability of FBXL5 is regulated in an iron- and oxygen-responsive manner, contingent upon the presence of its N-terminal domain. Here we present the atomic structure of the FBXL5 N terminus, a hemerythrin-like α-helical bundle fold not previously observed in mammalian proteins. The core of this domain employs an unusual assortment of amino acids necessary for the assembly and sensing properties of its diiron center. These regulatory features govern the accessibility of a mapped sequence required for proteasomal degradation of FBXL5. Detailed molecular and structural characterization of the ligand-responsive hemerythrin domain provides insights into the mechanisms by which FBXL5 serves as a unique mammalian metabolic sensor.
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.
authors.forename: Joel W
authors.initials: JW
authors.lastname: Thompson
authors.forename: Ameen A
authors.initials: AA
authors.lastname: Salahudeen
authors.forename: Srinivas
authors.initials: S
authors.lastname: Chollangi
authors.forename: Julio C
authors.initials: JC
authors.lastname: Ruiz
authors.forename: Chad A
authors.initials: CA
authors.lastname: Brautigam
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Makris
authors.forename: John D
authors.initials: JD
authors.lastname: Lipscomb
authors.forename: Diana R
authors.initials: DR
authors.lastname: Tomchick
authors.forename: Richard K
authors.initials: RK
authors.lastname: Bruick
mesh_terms: D018360:Crystallography, X-Ray; D004795:Enzyme Stability; D044783:F-Box Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D035942:Iron Regulatory Protein 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D013329:Structure-Activity Relationship; D043743:Ubiquitin-Protein Ligase Complexes; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D044783:F-Box Proteins; C521741:FBXL5 protein, human; D043743:Ubiquitin-Protein Ligase Complexes; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex; C546174:IREB2 protein, human; D035942:Iron Regulatory Protein 2