Molecular insights into prolyl and lysyl hydroxylation of fibrillar collagens in health and disease

Crit Rev Biochem Mol Biol. 2017 Feb;52(1):74-95. doi: 10.1080/10409238.2016.1269716. Epub 2016 Dec 23.


Collagen is a macromolecule that has versatile roles in physiology, ranging from structural support to mediating cell signaling. Formation of mature collagen fibrils out of procollagen α-chains requires a variety of enzymes and chaperones in a complex process spanning both intracellular and extracellular post-translational modifications. These processes include modifications of amino acids, folding of procollagen α-chains into a triple-helical configuration and subsequent stabilization, facilitation of transportation out of the cell, cleavage of propeptides, aggregation, cross-link formation, and finally the formation of mature fibrils. Disruption of any of the proteins involved in these biosynthesis steps potentially result in a variety of connective tissue diseases because of a destabilized extracellular matrix. In this review, we give a revised overview of the enzymes and chaperones currently known to be relevant to the conversion of lysine and proline into hydroxyproline and hydroxylysine, respectively, and the O-glycosylation of hydroxylysine and give insights into the consequences when these steps are disrupted.

Keywords: Bruck syndrome; Collagen; Ehlers–Danlos syndrome; connective tissue disorders; fibrosis; lysyl hydroxylation; osteogenesis imperfecta; prolyl hydroxylation.

Publication types

  • Review

MeSH terms

  • Animals
  • Arthrogryposis / metabolism
  • Arthrogryposis / pathology
  • Connective Tissue Diseases / metabolism
  • Connective Tissue Diseases / pathology
  • Ehlers-Danlos Syndrome / metabolism
  • Ehlers-Danlos Syndrome / pathology
  • Fibrillar Collagens / analysis
  • Fibrillar Collagens / metabolism*
  • Glycosylation
  • Humans
  • Hydroxylation
  • Hydroxylysine / analysis
  • Hydroxylysine / metabolism
  • Hydroxyproline / analysis
  • Hydroxyproline / metabolism
  • Lysine / analysis
  • Lysine / metabolism
  • Osteogenesis Imperfecta / metabolism
  • Osteogenesis Imperfecta / pathology
  • Proline / analysis
  • Proline / metabolism
  • Protein Folding


  • Fibrillar Collagens
  • Hydroxylysine
  • Proline
  • Lysine
  • Hydroxyproline

Supplementary concepts

  • Bruck syndrome 1
  • Bruck syndrome 2