CRTAP is required for prolyl 3- hydroxylation and mutations cause recessive osteogenesis imperfecta.
Prolyl hydroxylation is a critical posttranslational modification that affects structure, function, and turnover of target proteins. Prolyl 3-hydroxylation occurs at only one position in the triple-helical domain of fibrillar collagen chains, and its biological significance is unknown. CRTAP shares homology with a family of putative prolyl 3-hydroxylases (P3Hs), but it does not contain their common dioxygenase domain. Loss of Crtap in mice causes an osteochondrodysplasia characterized by severe osteoporosis and decreased osteoid production. CRTAP can form a complex with P3H1 and cyclophilin B (CYPB), and Crtap-/- bone and cartilage collagens show decreased prolyl 3-hydroxylation. Moreover, mutant collagen shows evidence of overmodification, and collagen fibrils in mutant skin have increased diameter consistent with altered fibrillogenesis. In humans, CRTAP mutations are associated with the clinical spectrum of recessive osteogenesis imperfecta, including the type II and VII forms. Hence, dysregulation of prolyl 3-hydroxylation is a mechanism for connective tissue disease.
Morello
Roy
R
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Bertin
Terry K
TK
Chen
Yuqing
Y
Hicks
John
J
Tonachini
Laura
L
Monticone
Massimiliano
M
Castagnola
Patrizio
P
Rauch
Frank
F
Glorieux
Francis H
FH
Vranka
Janice
J
Bächinger
Hans Peter
HP
Pace
James M
JM
Schwarze
Ulrike
U
Byers
Peter H
PH
Weis
MaryAnn
M
Fernandes
Russell J
RJ
Eyre
David R
DR
Yao
Zhenqiang
Z
Boyce
Brendan F
BF
Lee
Brendan
B
D000595:Amino Acid Sequence; D000818:Animals; D001851:Bone Diseases, Metabolic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001842:Bone and Bones / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D024022:Fibrillar Collagens / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018832:Molecular Chaperones; D008969:Molecular Sequence Data; D009154:Mutation; D010009:Osteochondrodysplasias / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010013:Osteogenesis Imperfecta / Q000235:genetics* / Q000378:metabolism; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors
C108053:CRTAP protein, human; C486354:Crtap protein, mouse; D016326:Extracellular Matrix Proteins; D024022:Fibrillar Collagens; D018832:Molecular Chaperones; D011506:Proteins; D012333:RNA, Messenger; D011393:Procollagen-Proline Dioxygenase; C030606:proline, 2-oxoglutarate 3-dioxygenase