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Review
. 2013;54(4-5):245-51.
doi: 10.3109/03008207.2013.800867. Epub 2013 Jun 21.

Collagen prolyl 3-hydroxylation: a major role for a minor post-translational modification?

David M Hudson  1 , David R Eyre
Affiliations
Review

Collagen prolyl 3-hydroxylation: a major role for a minor post-translational modification?

David M Hudson et al. Connect Tissue Res. 2013.

Abstract

Prolyl 3-hydroxylation is a rare but conserved post-translational modification in many collagen types and, when defective, may be linked to a number of human diseases with musculoskeletal and potentially ocular and renal pathologies. Prolyl 3-hydroxylase-1 (P3H1), the enzyme responsible for converting proline to 3-hydroxyproline (3Hyp) in type I collagen, requires the coenzyme CRTAP for activity. Mass spectrometric analysis showed that the Crtap-/- mouse was missing 3-hydroxyproline in type I collagen α-chains. This finding led to the discovery of mutations in genes encoding the P3H1 complex as a cause of recessively inherited osteogenesis imperfecta (brittle bone disease). Since then, many additional 3Hyp sites have been identified in various collagen types and classified based on observed substrate and tissue specificity. P3H1 is part of a family of gene products that also includes isoenzymes P3H2 and P3H3 as well as CRTAP and Sc65. It is believed these isoenzymes and coenzyme proteins have evolved different collagen substrate site and tissue specificities in their activities. The post-translational fingerprinting of collagens will be essential in understanding the basic role and extent of regulated variations of prolyl 3-hydroxylation in collagen. We believe that prolyl 3-hydroxylation is a functionally significant collagen post-translational modification and can be a cause of disease when absent.

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Figures

Figure 1
Figure 1
Model of the three classes of 3Hyp substrate sites identified in A-clade collagen. 3Hyp always occurs in the sequence Gly-3Hyp-4Hyp, A. We propose the Class 1 3Hyp (Pro986) functions in collagen fibril molecular packing, in which the subunits are in-register dimers staggered axially by D-periods, B. D-periodic spacing is evident between the Class 2 3Hyp residues (Pro470, Pro707 and Pro944) in the triple helix, C. Occurrence of the Class 3 3Hyp residues in the (GPP)n motif exhibited clear tissue specificity, with the modification occurring almost exclusively in tendon.
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