FKBP65-dependent peptidyl-prolyl isomerase activity potentiates the lysyl hydroxylase 2-driven collagen cross-link switch

摘要: Bruck Syndrome is a connective tissue disease associated with inactivating mutations in lysyl hydroxylase 2 (LH2/PLOD2) or FK506 binding protein 65 (FKBP65/FKBP10). However, the functional relationship between LH2 and FKBP65 remains unclear. Here, we postulated that peptidyl prolyl isomerase (PPIase) activity of positively modulates enzymatic critical for formation hydroxylysine-aldehyde derived intermolecular collagen cross-links (HLCCs). To test this hypothesis, analyzed Fkbp10-null –wild-type murine embryonic fibroblasts. Although levels did not change, deficiency significantly diminished HLCCs increased non-hydroxylated lysine-aldehyde–derived (LCCs), pattern consistent loss activity. The HLCC-to-LCC ratio was rescued FKBP65-deficient fibroblasts by reconstitution wild-type but mutant lacks intact PPIase domains. Findings from co-immunoprecipitation, protein-fragment complementation, co-immunofluorescence assays showed are part common complex. We conclude regulates LH2-mediated cross-linking. Because promotes fibrosis cancer metastasis, our findings suggest pharmacologic strategies to target may have complementary therapeutic activities.