Leprecan
Leprecan is a protein associated with osteogenesis imperfecta type VIII.
Leprecan is part of a superfamily of 2OG-Fe dioxygenase, along with DNA repair protein AlkB, and disease resistant EGL-9. The enzyme was found to be a type of hydroxylases used in the substrate formation of protein glycosylation.
Activities
Leprecan, a proteoglycan, has demonstrated prolyl hydroxylase activity; prolyl hydroxylases hydroxylate proline residues. Prolyl 3-hydroxylase 1, P3H1, forms a larger complex with CRTAP and cyclophilin B, CyPB, in the endoplasimic reticulum. The complex hydroxylates a single proline residue, Pro986, on collagen chains. Recessive forms of Osteogenesis Imperfecta are partly caused by a mutation in the LEPRE1 gene. The mutation in the gene encodes prolyl 3-hydroxylase 1. The malfunctioning prolyl 3-hydroxylase in leprecan leads to inappropriate collagen folding. This is due to the instability caused by the absence of hydroxyproline. Hydroxyproline is the product of hydroxylating a proline residue.
Structure
Leprecan, also known as P3H1, forms a tight complex with CRTAP and cyclophilin B, a collagen processing enzyme complex named PCP complex. Cryo-electron microscopy studies have revealed that the PCP complex consists of P3H1, CRTAP, and PPIB in a 1:1:1 stoichiometry. The complex features a "face-to-face" spatial arrangement, with the prolyl hydroxylation site of the C-terminal domain of P3H1 and the prolyl isomerization site of PPIB positioned at the "top" of the complex. Below these dual-catalytic sites lies an X-shaped base formed by CRTAP and the N-terminal domain of P3H1, which exhibit similar 3D foldings. The surface of the PCP complex also harbors several potential collagen-binding sites, as indicated by EM density corresponding to a synthetic peptide with the COL1A1 sequence. Furthermore, the PCP complex has the ability to dimerize, forming a hexameric structure.