Article

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

Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.
Journal of Biological Chemistry (impact factor: 4.77). 03/2012; 287(10):7357-65. DOI:10.1074/jbc.M111.308684 pp.7357-65
Source: PubMed

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.

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Keywords

atomic structure
 
bioavailable iron levels
 
Detailed molecular
 
diiron center
 
E3 ubiquitin ligase complex
 
FBXL5 N terminus
 
hemerythrin-like α-helical
 
iron homeostasis
 
iron metabolism
 
iron regulatory protein 2
 
ligand-responsive hemerythrin domain
 
Mammalian cells
 
mammalian proteins
 
mapped sequence
 
N-terminal domain
 
oxygen-responsive manner
 
proteasomal degradation
 
regulatory features
 
unique mammalian metabolic sensor
 
unusual assortment
 

Joel W Thompson