HSP47 and FKBP65 cooperate in the synthesis of type I procollagen

Abstract

Osteogenesis imperfecta (OI) is a genetic disorder that results in low bone mineral density and brittle bones. Most cases result from dominant mutations in the type I procollagen genes, but mutations in a growing number of genes have been identified that produce autosomal recessive forms of the disease. Among these include mutations in the genes SERPINH1 and FKBP10, which encode the type I procollagen chaperones HSP47 and FKBP65, respectively, and predominantly produce a moderately severe form of OI. Little is known about the biochemical consequences of the mutations and how they produce OI. We have identified a new OI mutation in SERPINH1 that results in destabilization and mislocalization of HSP47 and secondarily has similar effects on FKBP65. We found evidence that HSP47 and FKBP65 act cooperatively during posttranslational maturation of type I procollagen and that FKBP65 and HSP47 but fail to properly interact in mutant HSP47 cells. These results thus reveal a common cellular pathway in cases of OI caused by HSP47 and FKBP65 deficiency.

Analysis of FKBP10, SERPINH1, and SERPINF1 genes in patients with osteogenesis imperfecta

“…In the present study, we did not detect causative mutations in the SERPINH1 gene and there are few cases of reported mutations in SERPINH1 causing OI (Christiansen et al, 2010;Duran et al, 2015). Therefore, pathogenic changes in the SERPINH1 gene are thought to be very rare in OI patients.…”

Genetic causes and mechanisms of Osteogenesis Imperfecta

“…Mechanistically, Hsp47 regulates triple-helix stability via direct binding to specific arginine residues that lie at the interface between Hsp47 and collagen [66–68]. Loss of function mutations in HSP47 causes recessive OI due to aggregation and delayed secretion of procollagen molecules [69,70]. While Hsp47 is not directly involved in the post-translational modification of collagen, loss of function mutations of HSP47 (p.L326P) in a dog OI model caused overmodification of type I collagen and increased cross-linking without affecting 3Hyp (Pro986) [71].…”

“…This indicates that structural defects of collagen may contribute to abnormalities in post-translational modification. Given that FKBP65 and HSP47 co-eluted in a velocity sedimentation experiment [47] and were also shown to interact by proximity ligation assay, it is possible that HSP47 associates with the FKBP65/LH2 complex, albeit in a weak or transient fashion [69]. …”

Collagen Type I as a Ligand for Receptor-Mediated Signaling

“…After all the modifications are complete and the triple helix is formed, the molecules of procollagen are transported along microtubules, organized in the Golgi apparatus, and eventually secreted into the extracellular space [56]. In a homozygous patient with HSP47 missense mutation, it was demonstrated that HSP47, potentially acting in cooperation with immunophilin FKBP65, encoded by FKBP10, is important for proper trafficking of type I procollagen to the Golgi [57]. Mutations in FKBP10 also cause moderately severe osteogenesis imperfecta [58,59] with decreased collagen cross-linking, resulting in sparsity and disorder of collagen fibril deposition [60].…”