Mutations in PPIB (cyclophilin B) delay type I procollagen chain association and result in perinatal lethal to moderate osteogenesis imperfecta phenotypes
Mutations in PPIB (cyclophilin B) delay type I procollagen chain association and result in perinatal lethal to moderate osteogenesis imperfecta phenotypes
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DOI：
10.1093/hmg/ddr037
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发表时间：
2011-04-15
影响因子：
3.5
通讯作者：
Byers, Peter H.
中科院分区：
文献类型：
--
作者：
Pyott, Shawna M.;Schwarze, Ulrike;Byers, Peter H.
软骨相关蛋白 (CRTAP)、富含亮氨酸脯氨酸的蛋白聚糖 1 (LEPRE1) 和肽基脯氨酰顺反异构酶 B (PPIB) 基因的隐性突变会导致从围产期致命到严重变形成骨不全 (OI) 的表型。这些基因编码 CRTAP（由 CRTAP 编码）、脯氨酰 3-羟化酶 1（P3H1；由 LEPRE1 编码）和亲环蛋白 B（CYPB；由 PPIB 编码），它们存在于粗面内质网 (RER) 中，可以形成参与 I 型前胶原中脯氨酰 3-羟基化的复合物。 CYPB 是一种脯氨酰顺反异构酶，被认为可以驱动含脯氨酰的肽键形成三螺旋形成所需的反式构型。在这里，我们描述了在三名成骨不全症患者的细胞中发现的 PPIB 突变。从受影响最严重的婴儿中培养的真皮成纤维细胞会产生一些过度修饰的 I 型前胶原分子。 Pro α 1(I) 链组装成三聚体的速度很慢，异常的前胶原分子集中在 RER 中，并与蛋白质二硫键异构酶 (PDI) 和脯氨酰 4-羟化酶 1 (P4H1) 结合。这些发现表明，虽然 CYPB 在螺旋形成中发挥作用，但另一个作用是对 C 端前肽的折叠和三聚体形成。 PPIB、CRTAP 和 LEPRE1 突变的细胞中前胶原积累和 PDI/P4H1 结合程度不同，其中 PPIB 缺陷细胞中前胶原积累和 PDI/P4H1 结合程度最大，LEPRE1 缺陷细胞中前胶原积累和 PDI/P4H1 结合程度最小。这些发现表明，脯氨酰顺反异构酶可能需要有效折叠 C 端前肽富含脯氨酸的区域，以允许前 α 链缔合，并提示 CRTAP、P3H1 和 CYPB 在原胶原生物合成和 OI 发病机制中的作用顺序。
Recessive mutations in the cartilage-associated protein (CRTAP), leucine proline-enriched proteoglycan 1 (LEPRE1) and peptidyl prolyl cis-trans isomerase B (PPIB) genes result in phenotypes that range from lethal in the perinatal period to severe deforming osteogenesis imperfecta (OI). These genes encode CRTAP (encoded by CRTAP), prolyl 3-hydroxylase 1 (P3H1; encoded by LEPRE1) and cyclophilin B (CYPB; encoded by PPIB), which reside in the rough endoplasmic reticulum (RER) and can form a complex involved in prolyl 3-hydroxylation in type I procollagen. CYPB, a prolyl cis-trans isomerase, has been thought to drive the prolyl-containing peptide bonds to the trans configuration needed for triple helix formation. Here, we describe mutations in PPIB identified in cells from three individuals with OI. Cultured dermal fibroblasts from the most severely affected infant make some overmodified type I procollagen molecules. Pro alpha 1(I) chains are slow to assemble into trimers, and abnormal procollagen molecules concentrate in the RER, and bind to protein disulfide isomerase (PDI) and prolyl 4-hydroxylase 1 (P4H1). These findings suggest that although CYPB plays a role in helix formation another effect is on folding of the C-terminal propeptide and trimer formation. The extent of procollagen accumulation and PDI/P4H1 binding differs among cells with mutations in PPIB, CRTAP and LEPRE1 with the greatest amount in PPIB-deficient cells and the least in LEPRE1-deficient cells. These findings suggest that prolyl cis-trans isomerase may be required to effectively fold the proline-rich regions of the C-terminal propeptide to allow pro alpha chain association and suggest an order of action for CRTAP, P3H1 and CYPB in procollagen biosynthesis and pathogenesis of OI.