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Review
. 2019 Sep 13;63(3):325-335.
doi: 10.1042/EBC20180053. Print 2019 Sep 13.

Role of prolyl hydroxylation in the molecular interactions of collagens

Pekka Rappu  1 , Antti M Salo  2 , Johanna Myllyharju  2 , Jyrki Heino  3
Affiliations
Review

Role of prolyl hydroxylation in the molecular interactions of collagens

Pekka Rappu et al. Essays Biochem. .

Abstract

Co- and post-translational hydroxylation of proline residues is critical for the stability of the triple helical collagen structure. In this review, we summarise the biology of collagen prolyl 4-hydroxylases and collagen prolyl 3-hydroxylases, the enzymes responsible for proline hydroxylation. Furthermore, we describe the potential roles of hydroxyproline residues in the complex interplay between collagens and other proteins, especially integrin and discoidin domain receptor type cell adhesion receptors. Qualitative and quantitative regulation of collagen hydroxylation may have remarkable effects on the properties of the extracellular matrix and consequently on the cell behaviour.

Keywords: collagen; extracellular matrix; integrins; molecular interactions; prolyl hydroxylase.

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Conflict of interest statement

J.M. owns equity in FibroGen Inc., which develops HIF-P4H inhibitors as potential therapeutics. This company supports HIF-related research in the J.M. group.

Figures

Figure 1
Figure 1. Prolyl 4-hydroxylases (C-P4H-I, C-P4H-II and C-P4H-III) hydroxylate co- and post-translationally proline residues in collagens in a reaction that requires O2, 2-oxoglutarate, Fe++ and ascorbic acid
Proline hydroxylation is required for the stability of the collagenous triple helix at physiological temperatures.
Figure 2
Figure 2. Prolyl 3-hydroxylases hydroxylate selected proline residues in many, but not all collagens
Their substrate proline residues occur in the sequence -Pro-(4-Hyp)-Gly-. 3-Hyp is formed from the proline residue.
Figure 3
Figure 3. Hydroxylated proline residues participate in collagen fibril formation
They also promote interactions with cellular collagen receptors, such as integrins and DDRs, in a direct and an indirect manner. Many of the integrin and DDR recognition motifs in collagens contain 4-Hyp. Furthermore, GPO triplets may facilitate site-specific in vivo flexibility, and promote the binding of cellular receptors to motifs next to GPO-sites.
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