An iron-sulfur cluster plays a novel regulatory role in the iron-responsive element binding protein.
Post-transcriptional regulation of genes important in iron metabolism, ferritin and the transferrin receptor (TfR), is achieved through regulated binding of a cytosolic protein, the iron-responsive element binding protein (IRE-BP), to RNA stem-loop motifs known as iron-responsive elements (IREs). Binding of the IRE-BP represses ferritin translation and represses degradation of the TfR mRNA. The IRE-BP senses iron levels and accordingly modifies binding to IREs through a novel sensing mechanism. An iron-sulfur cluster of the IRE-BP reversibly binds iron; when cytosolic iron levels are depleted, the cluster becomes depleted of iron and the IRE-BP acquires the capacity to bind IREs. When cytosolic iron levels are replete, the IRE-BP loses RNA binding capacity, but acquires enzymatic activity as a functional aconitase. RNA binding and aconitase activity are mutually exclusive activities of the IRE-BP, and the state of the iron-sulfur cluster determines how the IRE-BP will function.
Rouault
T A
TA
Cell Biology and Metabolism Branch, National Institute of Child Health & Human Development, National Institutes of Health, Bethesda, MD 20892.
Haile
D J
DJ
Downey
W E
WE
Philpott
C C
CC
Tang
C
C
Samaniego
F
F
Chin
J
J
Paul
I
I
Orloff
D
D
Harford
J B
JB
D000154:Aconitate Hydratase / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D005293:Ferritins / Q000235:genetics*; D005786:Gene Expression Regulation; D006801:Humans; D007501:Iron / Q000378:metabolism; D035925:Iron-Regulatory Proteins; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D011990:Receptors, Transferrin / Q000235:genetics* / Q000378:metabolism; D013455:Sulfur / Q000378:metabolism
D035925:Iron-Regulatory Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D011990:Receptors, Transferrin; D013455:Sulfur; D005293:Ferritins; D007501:Iron; D000154:Aconitate Hydratase