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Review
. 2012 Sep;1823(9):1484-90.
doi: 10.1016/j.bbamcr.2012.02.003. Epub 2012 Feb 10.

Protein degradation and iron homeostasis

Joel W Thompson  1 , Richard K Bruick
Affiliations
Review

Protein degradation and iron homeostasis

Joel W Thompson et al. Biochim Biophys Acta. 2012 Sep.

Abstract

Regulation of both systemic and cellular iron homeostasis requires the capacity to sense iron levels and appropriately modify the expression of iron metabolism genes. These responses are coordinated through the efforts of several key regulatory factors including F-box and Leucine-rich Repeat Protein 5 (FBXL5), Iron Regulatory Proteins (IRPs), Hypoxia Inducible Factor (HIF), and ferroportin. Notably, the stability of each of these proteins is regulated in response to iron. Recent discoveries have greatly advanced our understanding of the molecular mechanisms governing iron-sensing and protein degradation within these pathways. It has become clear that iron's privileged roles in both enzyme catalysis and protein structure contribute to its regulation of protein stability. Moreover, these multiple pathways intersect with one another in larger regulatory networks to maintain iron homeostasis. This article is part of a Special Issue entitled: Cell Biology of Metals.

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Figures

Fig. 1
Fig. 1
Model of hepcidin (Hep) dependent and independent regulation of ferroportin (FPN).
Fig. 2
Fig. 2
Proteolytic regulation of HIF requires iron. (A) The HIF prolyl hydroxylase active site utilizes iron to bind dioxygen in order to hydroxylate proline residues on HIF-α. (B) Proteasomal degradation of HIF-α is mediated by the iron binding HIF prolyl hydroxylases that facilitate the interaction between pVHL and HIF-α.
Fig. 3
Fig. 3
Schematics of the diiron center from the canonical deoxy Hr (A) and the unorthodox FBXL5 Hr (B).
Fig. 4
Fig. 4
Structure of the FBXL5 Hr domain compared to the classical domain. Ribbon representations of the Hr domain from T. dyscritum (A; PDB code 1HMD) and the hemerythrin-like domain from H. sapien FBXL5 (B; PDB code 3V5Y).
Fig. 5
Fig. 5
Model of how the N-terminal Hr domain controls iron homeostasis through regulation of FBXL5 stability with concomitant control of IRP2 degradation.
Fig. 6
Fig. 6
Interconnections in the proteolytic pathways responsible for maintaining iron homeostasis. FBXL5 and HIF Prolyl Hydroxylases function as ostensible iron-sensors and promote the degradation of IRPs and HIF, respectively. FBXL5 is degraded when its Hr domain is prevented from binding iron. Ferroportin degradation is initiated upon hepcidin binding or following low cytosolic iron availability. These diverse regulatory factors are intertwined at multiple levels including IRPs negatively regulating HIF-α and ferroportin translation, and HIF-α inhibiting transcription of hepcidin.
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