Disentangling mechanisms involved in collagen pyridinoline cross-linking: The immunophilin FKBP65 is critical for dimerization of lysyl hydroxylase 2.
Collagens are subjected to extensive posttranslational modifications, such as lysine hydroxylation. Bruck syndrome (BS) is a connective tissue disorder characterized at the molecular level by a loss of telopeptide lysine hydroxylation, resulting in reduced collagen pyridinoline cross-linking. BS results from mutations in the genes coding for lysyl hydroxylase (LH) 2 or peptidyl-prolyl cis-trans isomerase (PPIase) FKBP65. Given that the immunophilin FKBP65 does not exhibit LH activity, it is likely that LH2 activity is somehow dependent on FKPB65. In this report, we provide insights regarding the interplay between LH2 and FKBP65. We found that FKBP65 forms complexes with LH2 splice variants LH2A and LH2B but not with LH1 and LH3. Ablating the catalytic activity of FKBP65 or LH2 did not affect complex formation. Both depletion of FKBP65 and inhibition of FKBP65 PPIase activity reduced the dimeric (active) form of LH2 but did not affect the binding of monomeric (inactive) LH2 to procollagen Iα1. Furthermore, we show that LH2A and LH2B cannot form heterodimers with each other but are able to form heterodimers with LH1 and LH3. Collectively, our results indicate that FKBP65 is linked to pyridinoline cross-linking by specifically mediating the dimerization of LH2. Moreover, FKBP65 does not interact with LH1 and LH3, explaining why in BS triple-helical hydroxylysines are not affected. Our results provide a mechanistic link between FKBP65 and the loss of pyridinolines and may hold the key to future treatments for diseases related to collagen cross-linking anomalies, such as fibrosis and cancer.
Matrix Accumulation, Tissue Repair, and Inflammation Research Group, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands; Epigenetic Editing Research Group, Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands r.a.f.gjaltema@umcg.nl r.a.bank@umcg.nl.
Rutger A F
RA
Gjaltema
Matrix Accumulation, Tissue Repair, and Inflammation Research Group, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands;
Miesje M
MM
van der Stoel
Matrix Accumulation, Tissue Repair, and Inflammation Research Group, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands;
Miriam
M
Boersema
Matrix Accumulation, Tissue Repair, and Inflammation Research Group, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands; r.a.f.gjaltema@umcg.nl r.a.bank@umcg.nl.
Ruud A
RA
Bank
D000596:Amino Acids / Q000737:chemistry* / Q000378:metabolism; D001176:Arthrogryposis / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D003094:Collagen / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D024042:Collagen Type I / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D003432:Cross-Linking Reagents / Q000737:chemistry*; D019281:Dimerization; D006801:Humans; D010013:Osteogenesis Imperfecta / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000378:metabolism*
D000596:Amino Acids; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D003432:Cross-Linking Reagents; C015484:pyridinoline; D003094:Collagen; C479138:PLOD2 protein, human; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase; D022021:Tacrolimus Binding Proteins; C110054:FKBP10 protein, human
Bruck syndrome; FKBP65; collagen cross‐linking; fibrosis; lysyl hydroxylase