Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
, 45 (2), 106-24

Prolyl 4-hydroxylase

Affiliations
Review

Prolyl 4-hydroxylase

Kelly L Gorres et al. Crit Rev Biochem Mol Biol.

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 alpha, which plays a key role in sensing molecular oxygen, and could act on inhibitory kappaB 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.

Figures

Figure 1
Figure 1
Catalysis by P4H and its consequences. (A) Reaction catalyzed by P4H. (B) The 4R hydroxyl group makes the prolyl nitrogen more acidic (Eberhardt et al., 1996) and increases its preference for a Cγ-exo ring pucker and trans peptide bond (Bretscher et al., 2001; DeRider et al., 2002).
Figure 2
Figure 2
Three-dimensional structure of a fragment of a collagen triple helix composed of (Pro–Hyp–Gly)n strands (PDB 1v4f (Okuyama et al., 2004)). Inset: Close-up of a Hyp residue showing the characteristic Cγ-exo ring pucker.
Figure 3
Figure 3
Putative mechanism of the reaction catalyzed by human P4H. The configuration of the active-site residues around the iron is not known.
Figure 4
Figure 4
Surfactant proteins A and D (SP-A and SP-D). SP-A forms a “bunch-of-tulips” overall structure composed of 18 proteins with 6 sets of triple helices. SP-D forms from 12 proteins with 4 sets of triple helices. Figure adapted with permission from (Kishore et al., 2006).
Figure 5
Figure 5
Hypoxia sensing pathway. Under normoxia, hypoxia inducible factor-1α (HIF-1α) is hydroxylated by prolyl hydroxylase domain-containing proteins (PHDs), and then recognized for ubiquitination by pVHL E3 ligase and targeted for degradation by the proteasome. During hypoxia, HIF-1α is not degraded and translocates to the nucleus. There, HIF-1α works with HIF-1β, E1A binding protein p300, and CREB binding protein (CBP) to activate the transcription of genes controlled by the hypoxia response element (HRE).
Figure 6
Figure 6
Role of Hyp in oxygen sensing. The three-dimensional structure of pVHL·elonginB·elonginC complex with a peptide from HIF-1α (PDB 1lqb (Chowdhury et al., 2008)). Hydrogen bonds between the hydroxyl group of Hyp564 of HIF-1α and Ser111 and His115 of pVHL direct the degradation of HIF-1α. Figure adapted with permission from (Chowdhury et al., 2008).
Figure 7
Figure 7
Three-dimensional structures of prolyl 4-hydroxylases (brown) bound to peptide substrates (gray). (A) Cr-P4H-1 with (Pro–Ser)5 and Zn(II) in its active site (PDB 3gze). (B) PHD2 with a HIF-derived peptide and Mn(II) in its active site (PDB 3hqr). In both substrates, the bound proline residue adopts a Cγ-endo ring pucker.
Figure 8
Figure 8
Three-dimensional structures of three prolyl hydroxylases and two related enzymes. From the top left are PHD2 (PDB 2g1m (McDonough et al., 2006)), Cr-P4H-1 (2jig (Koski et al., 2007)), and proline 3-hydroxylase (1e5s (Clifton et al., 2001)). From the bottom left are the asparaginyl hydroxylase FIH (1h2n (Elkins et al., 2003)) and halogenase SyrB2 (2fct (Blasiak et al., 2006)). Proteins are colored by secondary structure with helices in dark red and sheets in tan. The active-site iron is in orange. The 2-His–1-Asp residues that coordinate the metal are in light blue. The zinc in Cr-P4H-1 is in gray; the chloride in SyrB2 is in green. (See colour version of this figure online at www.informahealthcare.com/bmg)

Similar articles

See all similar articles

Cited by 127 PubMed Central articles

See all "Cited by" articles

Publication types

LinkOut - more resources

Feedback