Prolyl 4-hydroxylase

Abstract

Posttranslational modifications can cause profound changes in protein function. Typically, these modifications are reversible, and thus provide a biochemical on-off switch. In contrast, proline residues are the substrates for an irreversible reaction that is the most common posttranslational modification in humans. This reaction, which is catalyzed by prolyl 4-hydroxylase (P4H), yields (2S,4R)-4-hydroxyproline (Hyp). The protein substrates for P4Hs are diverse. Likewise, the biological consequences of prolyl hydroxylation vary widely, and include altering protein conformation and protein–protein interactions, and enabling further modification. The best known role for Hyp is in stabilizing the collagen triple helix. Hyp is also found in proteins with collagen-like domains, as well as elastin, conotoxins, and argonaute 2. A prolyl hydroxylase domain protein acts on the hypoxia inducible factor α, which plays a key role in sensing molecular oxygen, and could act on inhibitory κB kinase and RNA polymerase II. P4Hs are not unique to animals, being found in plants and microbes as well. Here, we review the enzymic catalysts of prolyl hydroxylation, along with the chemical and biochemical consequences of this subtle but abundant posttranslational modification.

Keywords:

• Non-heme iron dioxygenase
• proline
• hydroxyproline
• posttranslational modification
• collagen

Acknowledgements

K.L.G. was supported by Chemistry–Biology Interface Training Grant T32 BM008505 (NIH). Work in our laboratory on prolyl 4-hydroxylases is supported by grant R01 AR044276 (NIH).

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content of this paper.

Editor: Michael M. Cox