EGLN3/PHD3: Proteins and Enzymes

Egl nine homolog 3 (EGLN3), also known as PHD3, is a widely expressed 27 kDa enzyme that hydroxylates proline residues on target proteins including HIF-1 alpha. HIF-1 is an alpha/beta heterodimeric transcriptional activator that upregulates genes involved in mitigating the effects of hypoxia. Normally, and in the presence of abundant oxygen, the HIF-1 alpha-chain is hydroxylated by PHD family members, which results in its ubiquitylation and degradation. Under low oxygen tension, EGLN3 activity is decreased, the HIF-1 alpha subunit is retained, and HIF-1 activates genes. EGLN3 also hydroxylates and promotes the degradation of the beta-2-adrenergic receptor, promotes myogenic differentiation, promotes apoptosis via caspase activation, and blocks tumor angiogenesis. EGLN3 forms homomultimers and heteromultimers with other EGLN proteins, and this is enhanced during hypoxia. EGLN3 contains one iron 2-oxoglutarate (Fe2OG) dioxygenase domain (aa 278-376), an iron-binding site (Asp137 and His196), and a 2-oxoglutarate-binding site (Arg205).