Leprecan (P3H1) is a protein associated with

osteogenesis imperfecta Osteogenesis imperfecta (; OI), colloquially known as brittle bone disease, is a group of genetic disorders that all result in bones that bone fracture, break easily. The range of symptoms—on the skeleton as well as on the body's other Or ...

type VIII. Leprecan is part of a superfamily of 2OG-Fe(II) 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 Proteoglycans are proteins that are heavily glycosylated. The basic proteoglycan unit consists of a "core protein" with one or more covalently attached glycosaminoglycan (GAG) chain(s). The point of attachment is a serine (Ser) residue to w ...

, has demonstrated prolyl hydroxylase activity; prolyl hydroxylases hydroxylate

proline Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the p ...

residues. Prolyl 3-hydroxylase 1, P3H1, forms a larger complex with CRTAP and

cyclophilin Cyclophilins (CYPs) are a family of proteins named after their ability to bind to ciclosporin (cyclosporin A), an immunosuppressant which is usually used to suppress rejection after internal organ transplants. They are found in all domains of lif ...

B, CyPB, in the endoplasimic reticulum. The complex hydroxylates a single proline residue, Pro986, on

collagen Collagen () is the main structural protein in the extracellular matrix of the connective tissues of many animals. It is the most abundant protein in mammals, making up 25% to 35% of protein content. Amino acids are bound together to form a trip ...

chains. Recessive forms of

Osteogenesis Imperfecta Osteogenesis imperfecta (; OI), colloquially known as brittle bone disease, is a group of genetic disorders that all result in bones that bone fracture, break easily. The range of symptoms—on the skeleton as well as on the body's other Or ...

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 (2''S'',4''R'')-4-Hydroxyproline, or L-hydroxyproline ( C5 H9 O3 N), is an amino acid, abbreviated as Hyp or O, ''e.g.'', in Protein Data Bank. Structure and discovery In 1902, Hermann Emil Fischer isolated hydroxyproline from hydrolyzed gela ...

. Hydroxyproline is the product of hydroxylating a proline residue.

Structure

Leprecan, also known as P3H1, forms a tight complex with CRTAP and

B (

PPIB Peptidyl-prolyl cis-trans isomerase B is an enzyme that is encoded by the ''PPIB'' gene. As a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family, this protein catalyzes the cis-trans isomerization of proline imidic peptide bonds, w ...

), a collagen processing enzyme complex named PCP complex (P3H1-CRTAP-PPIB). Cryo-electron microscopy (cryo-EM) 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.

References

External links

* {{Fibrous proteins