TY - JOUR
T1 - F-box and leucine-rich repeat protein 5 (FBXL5)
T2 - Sensing intracellular iron and oxygen
AU - Ruiz, Julio C.
AU - Bruick, Richard K.
N1 - Funding Information:
We thank Thomas Scheuermann and Mariano Ruiz for assistance with figure preparation. R.K.B. is the Michael L. Rosenberg Scholar in Medical Research and was supported by a Career Award in the Biomedical Sciences from the Burroughs Wellcome Fund , the Robert A. Welch Foundation ( I-1568 ), and the National Institutes of Health ( HL102481 ).
PY - 2014/4
Y1 - 2014/4
N2 - Though essential for many vital biological processes, excess iron results in the formation of damaging reactive oxygen species (ROS). Therefore, iron metabolism must be tightly regulated. F-box and leucine-rich repeat protein 5 (FBXL5), an E3 ubiquitin ligase subunit, regulates cellular and systemic iron homeostasis by facilitating iron regulatory protein 2 (IRP2) degradation. FBXL5 possesses an N-terminal hemerythrin (Hr)-like domain that mediates its own differential stability by switching between two different conformations to communicate cellular iron availability. In addition, the FBXL5-Hr domain also senses O2 availability, albeit by a distinct mechanism. Mice lacking FBXL5 fail to sense intracellular iron levels and die in utero due to iron overload and exposure to damaging levels of oxidative stress. By closely monitoring intracellular levels of iron and oxygen, FBLX5 prevents the formation of conditions that favor ROS formation. These findings suggest that FBXL5 is essential for the maintenance of iron homeostasis and is a key sensor of bioavailable iron. Here, we describe the iron and oxygen sensing mechanisms of the FBXL5 Hr-like domain and its role in mediating ROS biology.
AB - Though essential for many vital biological processes, excess iron results in the formation of damaging reactive oxygen species (ROS). Therefore, iron metabolism must be tightly regulated. F-box and leucine-rich repeat protein 5 (FBXL5), an E3 ubiquitin ligase subunit, regulates cellular and systemic iron homeostasis by facilitating iron regulatory protein 2 (IRP2) degradation. FBXL5 possesses an N-terminal hemerythrin (Hr)-like domain that mediates its own differential stability by switching between two different conformations to communicate cellular iron availability. In addition, the FBXL5-Hr domain also senses O2 availability, albeit by a distinct mechanism. Mice lacking FBXL5 fail to sense intracellular iron levels and die in utero due to iron overload and exposure to damaging levels of oxidative stress. By closely monitoring intracellular levels of iron and oxygen, FBLX5 prevents the formation of conditions that favor ROS formation. These findings suggest that FBXL5 is essential for the maintenance of iron homeostasis and is a key sensor of bioavailable iron. Here, we describe the iron and oxygen sensing mechanisms of the FBXL5 Hr-like domain and its role in mediating ROS biology.
KW - FBXL5
KW - Hemerythrin
KW - Iron
KW - Iron regulatory proteins
KW - Oxygen
KW - Reactive oxygen species
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U2 - 10.1016/j.jinorgbio.2014.01.015
DO - 10.1016/j.jinorgbio.2014.01.015
M3 - Article
C2 - 24508277
AN - SCOPUS:84897107855
SN - 0162-0134
VL - 133
SP - 73
EP - 77
JO - Journal of Inorganic Biochemistry
JF - Journal of Inorganic Biochemistry
ER -