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BBB Seminar: Johanna Myllyharju

4-Hydroxyprolines, from collagens to the regulation of oxygen homeostasis and beyond

Johanna Myllyharju,
Oulu Center for Cell-Matrix Research, Biocenter Oulu and Department of Medical Biochemistry and Molecular Biology, University of Oulu, Finland

Hydroxylation of proline residues by prolyl 4-hydroxylases (P4Hs) has been known for decades to have a critical role in extracellular matrix synthesis. Hydroxylation of collagen polypeptide chains is catalysed by an endoplasmic reticulum lumenal collagen P4H family that consists of three isoenzymes in vertebrates. This modification is essential for proper folding and thermal stability of the triple-helical collagen molecules. P4Hs are 2-oxoglutarate dioxygenases and require Fe2+, 2-oxoglutarate, O2 and ascorbate for catalysis. In 2001, a novel role for prolyl 4-hydroxylation was discovered as it was shown to provide a major oxygen sensing mechanism in cells and tissues. Oxygen homeostasis is a critical aspect of normal development and physiology, and many pathological processes are associated with lowered oxygen levels. The response of cells to hypoxia is chiefly mediated by the hypoxia-inducible transcription factor HIF, an αβ dimer, that has a pivotal role in the induction of numerous genes involved in the mediation of survival and adaptive responses to hypoxia. The stability of the HIF-a subunit is regulated by prolyl 4-hydroxylation catalysed by a cytoplasmic and nuclear P4H family, the HIF-P4Hs, with three isoenzymes in vertebrates. Hydroxylation HIF-a mediates its interaction with the von Hippel-Lindau E3 ubiquitin ligase complex, which targets it for rapid proteasomal degradation in normoxia. Hypoxia inhibits HIF-P4Hs, which leads to stabilisation of HIF-α, and assembly of an active αβ dimer that can induce several genes involved in haematopoesis, angiogenesis, iron transport, glucose utilisation, cell proliferation, survival and apoptosis. In recent years it has been discovered that prolyl 4-hydroxylation has even more diverse biological functions, which will be discussed in the presentation.

Host: Rolf Kåre Reed, Department of Biomedicine