CRTAP is required for prolyl 3-hydroxylation and mutations cause recessive osteogenesis imperfecta
CRTAP is required for prolyl 3-hydroxylation and mutations cause recessive osteogenesis imperfecta
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DOI：
10.1016/j.cell.2006.08.039
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发表时间：
2006-10-20
期刊：
影响因子：
64.5
通讯作者：
Lee, Brendan
中科院分区：
文献类型：
--
作者：
Morello, Roy;Bertin, Terry K.;Lee, Brendan
脯氨酰羟基化是一种重要的翻译后修饰，它影响靶蛋白的结构、功能和周转。脯氨酰3-羟基化仅发生在纤维状胶原蛋白链的三螺旋结构域中的一个位置，其生物学意义尚不清楚。CRTAP与一个推定的脯氨酰3-羟化酶（P3 H）家族具有同源性，但不包含它们共同的双加氧酶结构域。Crtap在小鼠中的缺失导致骨软骨发育不良，其特征在于严重的骨质疏松症和类骨质生成减少。CRTAP可与P3 H1和亲环素B（CYPB）形成复合物，并且Crtap（-/-）骨和软骨胶原显示脯氨酰3-羟基化降低。此外，突变型胶原显示出过度修饰的证据，并且突变型皮肤中的胶原原纤维具有与改变的原纤维形成一致的增加的直径。在人类中，CRTAP突变与隐性成骨不全的临床谱相关，包括II型和VII型。因此，脯氨酰3-羟基化的失调是结缔组织病的一种机制。
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 osteo-chondrodysplasia 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.