Structural and molecular characterization of iron-sensing hemerythrin-like domain within F-box and leucine-rich repeat protein 5 (FBXL5)

Joel W. Thompson, Ameen A. Salahudeen, Srinivas Chollangi, Julio C. Ruiz, Chad A. Brautigam, Thomas M. Makris, John D Lipscomb, Diana R. Tomchick, Richard K. Bruick

Research output: Contribution to journalArticle

40 Citations (Scopus)

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 theFBXL5Nterminus, a hemerythrin-likeα-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.

Original languageEnglish (US)
Pages (from-to)7357-7365
Number of pages9
JournalJournal of Biological Chemistry
Volume287
Issue number10
DOIs
StatePublished - Mar 2 2012

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Hemerythrin
Iron
Iron Regulatory Protein 2
Ubiquitin-Protein Ligases
Regulator Genes
Metabolism
Homeostasis
Genes
Cells
Oxygen
Ligands
Amino Acids
Degradation
leucine-rich repeat proteins
Sensors
Proteins

Cite this

Thompson, J. W., Salahudeen, A. A., Chollangi, S., Ruiz, J. C., Brautigam, C. A., Makris, T. M., ... Bruick, R. K. (2012). Structural and molecular characterization of iron-sensing hemerythrin-like domain within F-box and leucine-rich repeat protein 5 (FBXL5). Journal of Biological Chemistry, 287(10), 7357-7365. https://doi.org/10.1074/jbc.M111.308684

Structural and molecular characterization of iron-sensing hemerythrin-like domain within F-box and leucine-rich repeat protein 5 (FBXL5). / Thompson, Joel W.; Salahudeen, Ameen A.; Chollangi, Srinivas; Ruiz, Julio C.; Brautigam, Chad A.; Makris, Thomas M.; Lipscomb, John D; Tomchick, Diana R.; Bruick, Richard K.

In: Journal of Biological Chemistry, Vol. 287, No. 10, 02.03.2012, p. 7357-7365.

Research output: Contribution to journalArticle

Thompson, JW, Salahudeen, AA, Chollangi, S, Ruiz, JC, Brautigam, CA, Makris, TM, Lipscomb, JD, Tomchick, DR & Bruick, RK 2012, 'Structural and molecular characterization of iron-sensing hemerythrin-like domain within F-box and leucine-rich repeat protein 5 (FBXL5)', Journal of Biological Chemistry, vol. 287, no. 10, pp. 7357-7365. https://doi.org/10.1074/jbc.M111.308684
Thompson, Joel W. ; Salahudeen, Ameen A. ; Chollangi, Srinivas ; Ruiz, Julio C. ; Brautigam, Chad A. ; Makris, Thomas M. ; Lipscomb, John D ; Tomchick, Diana R. ; Bruick, Richard K. / Structural and molecular characterization of iron-sensing hemerythrin-like domain within F-box and leucine-rich repeat protein 5 (FBXL5). In: Journal of Biological Chemistry. 2012 ; Vol. 287, No. 10. pp. 7357-7365.
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