Type I collagen synthesis in the context of osteogenesis imperfecta (WP4786)

Type I collagen — the major protein component of the extracellular matrix in bone, skin and tendon — is mainly secreted by osteoblasts, dermal fibroblasts and tenocytes. Despite the relatively simple structure of the collagen triple helix, the biosynthesis of type I procollagen is extremely complex, involving multiple steps and requiring an ensemble of proteins for post-translational modifications, folding, transport, secretion and quality control. The COL1A1 and COL1A2 transcripts are translated in the rough endoplasmic reticulum (rER), and the α(I)‑chains undergo a series of post-translational modifications. Helical prolines in position Y of the Gly-Xaa-Yaa repeat are hydroxylated in position C4 by prolyl 4‑hydroxylase 1 (P4H1), whereas specific prolines in the X positions are 3‑hydroxylated by P3H1 and P3H2. Some lysine residues are hydroxylated by lysyl hydroxylases (LH1 and LH2, encoded by PLOD1 and PLOD2 respectively), and glycosylation of hydroxylysines into galactosyl-hydroxylysine and glucosyl-galactosyl-hydroxylysine is catalysed by procollagen galactosyltransferase 1 and procollagen glucosyltransferase 1. After synthesis of the carboxy-terminal propeptide, it forms intra-chain disulfide bonds and remains attached to the rER membrane. Selection and association of the correct chains into a triple helix occur by diffusion of the C-propeptides attached to the rER membrane. A nucleus for triple helix formation is formed that staggers the chains in the correct order and initiates triple helix formation. Protein disulfide isomerase catalyses inter-chain disulfide bond formation, which stabilize the folding nucleus. Hydroxylation of proline residues and some lysine residues continues and triple helix formation proceeds from the C-terminal end towards the amino-terminal end. During this phase, 65 kDa FK506‑binding protein (FKBP65; encoded by FKBP10) and a complex formed by P3H1 — CRTAP– PPIase B (peptidyl-prolyl cis–trans isomerase B) — seem to play a crucial part. The complex is involved in the Hydroxylation of proline 986 of the collagen α1(I)-chain and α1(II)-chain and proline 707 of the α2(I)-chain, which are thought to be important for supramolecular assembly of collagen fibrils and to serve as binding sites for chaperones or small leucine-rich proteoglycans. Beyond its prolyl 3‑hydroxylase activity, the complex functions as a PPIase and chaperone for collagen folding. Indeed, the fast propagation of the triple helix requires the isomerization of cis peptide bonds that convert proline residues into trans configuration, mainly by PPIase B24. When most of the helix is folded, the N-propeptides associate and form the small triple helix within this domain. The newly formed triple helix is stabilized by serpin H1 (also known as HSP47; encoded by SERPINH1) and FKBP65. Further modifications occur during transport from the rER to the Golgi apparatus in special coat protein complex vesicles that contain melanoma inhibitory activity protein 3 (also known as TANGO1, encoded by MIA) and through the Golgi stack by cisternal maturation. Serpin H1 also has binding sites along the helical portion of the molecule and assists shuttling of folded collagen into the cis-Golgi. These biosynthetic steps depend on a proper rER environment (for example, optimal calcium levels and redox potential), and the quality-control mechanisms can lead to the activation of the unfolded protein response using the ER-associated degradation pathway or the autophagy-mediated lysosomal degradation system to eliminate molecules that were not properly folded. Once secreted, the propeptides of procollagen are cleaved by a disintegrin and metalloproteinase with thrombospondin motifs 2 (ADAMTS2) and bone morphogenetic protein 1 (BMP1) into mature type I collagen. This initiates collagen fibre formation and these fibrils are stabilized by crosslink formation, in which certain lysine and hydroxylysine residues in the triple helix and the telopeptides are oxidized by lysyl oxidases and converted into allysine and hydroxyallysine. These residues then initially form divalent crosslinks that convert into mature trivalent pyridinoline and pyrrole crosslinks to stabilize the fibril structure in tissues. Bone formation consists of the secretion of bone extracellular matrix components (mainly type I collagen) by osteoblasts. The unmineralized bone matrix (osteoid) subsequently becomes mineralized. In addition, osteoblasts and osteocytes release many cytokines, including receptor activator of nuclear factor-κB ligand (RANKL; also known as TNFSF11) and osteoprotegerin (OPG, encoded by TNFRSF11B), which regulate bone resorption by osteoclasts. RANKL acts on osteoclast precursor cells by binding to receptor activator of nuclear factor-κB (RANK; also known as TNFRSF11A) on their surface, thereby favouring their differentiation to osteoclasts. OPG, by interacting with RANKL, prevents the binding of RANKL to RANK. Some osteoblasts become embedded in the mineralized bone matrix and differentiate to osteocytes, which produce, among other factors, sclerostin, an inhibitor of the WNT pathway that is known to stimulate bone formation by stimulating osteoblast activity. Linked with a dotted arrow to the GeneProduct nodes are diseases caused by mutation in the respective gene. Adapted from [5]
last edited

Authors

Rlee, Khanspers, Egonw, Azankl, and Eweitz

Cited In

Organism

Homo sapiens

Communities

Skeletal Dysplasia

Annotations

Disease Ontology: osteogenesis imperfecta

Participants

Label Type Compact Identifier
CREB3L1 GeneProduct ensembl:ENSG00000157613
ITPR1 GeneProduct ensembl:ENSG00000150995
CRTAP GeneProduct ensembl:ENSG00000170275
SP7 GeneProduct ensembl:ENSG00000170374
P4HA2 GeneProduct ensembl:ENSG00000072682
P4HA1 GeneProduct ensembl:ENSG00000122884
TNFRSF11B GeneProduct ensembl:ENSG00000164761
TNFRSF11A GeneProduct ensembl:ENSG00000141655
MBTPS1 GeneProduct ensembl:ENSG00000140943
FZD1 GeneProduct ensembl:ENSG00000157240
BMP1 GeneProduct ensembl:ENSG00000168487
TNFSF11 GeneProduct ensembl:ENSG00000120659
LRP6 GeneProduct ensembl:ENSG00000070018
PLOD2 GeneProduct ensembl:ENSG00000152952
ADAMTS2 GeneProduct ensembl:ENSG00000087116
PLOD1 GeneProduct ensembl:ENSG00000083444
WNT1 GeneProduct ensembl:ENSG00000125084
K+ Metabolite chebi:29103
TMEM38B GeneProduct ensembl:ENSG00000095209
LOX GeneProduct ensembl:ENSG00000113083
SERPINH1 GeneProduct ensembl:ENSG00000149257
COL1A1 GeneProduct ensembl:ENSG00000108821
P3H1 GeneProduct ensembl:ENSG00000117385
P3H1 GeneProduct ensembl:ENSG00000117385
LRP5 GeneProduct ensembl:ENSG00000162337
SERPINF1 GeneProduct ensembl:ENSG00000132386
MIA3 GeneProduct ensembl:ENSG00000154305
Ca2+ Metabolite chebi:29108
FKBP10 GeneProduct ensembl:ENSG00000141756
SERPINH1 GeneProduct ensembl:ENSG00000149257
COL1A2 GeneProduct ensembl:ENSG00000164692
MBTPS2 GeneProduct ensembl:ENSG00000012174
COLGALT1 GeneProduct ensembl:ENSG00000130309
PPIB GeneProduct ensembl:ENSG00000166794
P4HB GeneProduct ensembl:ENSG00000185624
IFITM5 GeneProduct ensembl:ENSG00000206013
COL1A1 GeneProduct ensembl:ENSG00000108821
Ca2+ Metabolite chebi:29108
K+ Metabolite chebi:29103
P3H2 GeneProduct ensembl:ENSG00000090530

References

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  4. Forlino A, Cabral WA, Barnes AM, Marini JC. New perspectives on osteogenesis imperfecta. Nat Rev Endocrinol. 2011 Jun 14;7(9):540–57. PubMed Europe PMC Scholia
  5. Marini JC, Forlino A, Bächinger HP, Bishop NJ, Byers PH, Paepe AD, et al. Osteogenesis imperfecta. Nat Rev Dis Primers. 2017 Aug 18;3:17052. PubMed Europe PMC Scholia