Leprecan Explained

Leprecan is a protein associated with osteogenesis imperfecta^[1] 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.^[2]

Activities

Leprecan, a proteoglycan, has demonstrated prolyl hydroxylase activity; prolyl hydroxylases hydroxylate proline residues.^[3] 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.^[4] 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.^[5]

Structure

Leprecan, also known as P3H1, forms a tight complex with CRTAP and cyclophilin B (PPIB), 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.^[6] 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.

Notes and References

1. Cabral WA, Chang W, Barnes AM, Weis M, Scott MA, Leikin S, Makareeva E, Kuznetsova NV, Rosenbaum KN, Tifft CJ, Bulas DI, Kozma C, Smith PA, Eyre DR, Marini JC . Prolyl 3-hydroxylase 1 deficiency causes a recessive metabolic bone disorder resembling lethal/severe osteogenesis imperfecta . Nature Genetics . 39 . 3 . 359–65 . March 2007 . 17277775 . 10.1038/ng1968 . 7510175 .
2. Aravind L, Koonin EV . The DNA-repair protein AlkB, EGL-9, and leprecan define new families of 2-oxoglutarate- and iron-dependent dioxygenases . Genome Biology . 2 . 3 . RESEARCH0007 . 2001-02-19 . 11276424 . 30706 . 10.1186/gb-2001-2-3-research0007 . free .
3. Lauer M, Scruggs B, Chen S, Wassenhove-McCarthy D, McCarthy KJ . Leprecan distribution in the developing and adult kidney . English . Kidney International . 72 . 1 . 82–91 . July 2007 . 17495866 . 10.1038/sj.ki.5002269 . free .
4. Chang W, Barnes AM, Cabral WA, Bodurtha JN, Marini JC . Prolyl 3-hydroxylase 1 and CRTAP are mutually stabilizing in the endoplasmic reticulum collagen prolyl 3-hydroxylation complex . Human Molecular Genetics . 19 . 2 . 223–34 . January 2010 . 19846465 . 2796888 . 10.1093/hmg/ddp481 .
5. Homan EP, Lietman C, Grafe I, Lennington J, Morello R, Napierala D, Jiang MM, Munivez EM, Dawson B, Bertin TK, Chen Y, Lua R, Lichtarge O, Hicks J, Weis MA, Eyre D, Lee BH . Differential effects of collagen prolyl 3-hydroxylation on skeletal tissues . PLOS Genetics . 10 . 1 . e1004121 . January 2014 . 24465224 . 3900401 . 10.1371/journal.pgen.1004121 . free .
6. Li . Wenguo . Peng . Junjiang . Yao . Deqiang . Rao . Bing . Xia . Ying . Wang . Qian . Li . Shaobai . Cao . Mi . Shen . Yafeng . Ma . Peixiang . Liao . Rijing . Qin . An . Zhao . Jie . Cao . Yu . 2024-09-08 . The structural basis for the collagen processing by human P3H1/CRTAP/PPIB ternary complex . Nature Communications . en . 15 . 1 . 7844 . 10.1038/s41467-024-52321-6 . 2041-1723. 11381544 .