Prodomains of Transforming Growth Factor β (TGFβ) Superfamily Members Specify Different Functions
Prodomains of Transforming Growth Factor β (TGFβ) Superfamily Members Specify Different Functions
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转化生长因子 β (TGFβ) 超家族成员的前结构域指定不同的功能
DOI：
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发表时间：
2010
影响因子：
4.8
通讯作者：
L. Sakai
中科院分区：
文献类型：
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作者：
G. Sengle;R. Ono;Takako Sasaki;L. Sakai
TGFβ超家族成员原结构域的具体功能在很大程度上是未知的。已知TGFβ-1-3的原结构域与潜在的tgf β结合蛋白之间，以及BMP-2、-4、-7和-10的原结构域与GDF-5和纤维蛋白之间的相互作用，这提高了潜在的tgf β结合蛋白和纤维蛋白可能介导与该超家族所有其他原结构域相互作用的可能性。这项研究验证了这种可能性。结果表明BMP-5的原结构域与纤维蛋白-1和-2的n端相互作用的位点与其他骨形态发生蛋白的结合位点相似。然而，相比之下，GDF-8（肌肉生长抑制素）的原结构域与perlecan的糖胺聚糖侧链相互作用。GDF-8原结构域的结合位点可能是存在于perlecan结构域v上的硫酸肝素链。这些结果支持并扩展了TGFβ超家族原结构域将其生长因子二聚体靶向细胞外基质大分子的新兴概念。此外，对原域·生长因子复合物进行了生化研究，以确定无活性复合物。对于超家族的一些成员，原结构域在非活性复合体中与其生长因子二聚体非共价结合；对于另一些，原结构域·生长因子复合物是有活性的，即使原结构域与其生长因子二聚体非共价结合。结果表明，与BMP-4、-5和-7原结构域相比，BMP-10原结构域可以抑制BMP-10生长因子的生物活性，表明BMP-10复合物类似于tgf - β和GDF-8复合物，可以通过裂解相关原结构域来激活。
The specific functions of the prodomains of TGFβ superfamily members are largely unknown. Interactions are known between prodomains of TGFβ-1–3 and latent TGFβ-binding proteins and between prodomains of BMP-2, -4, -7, and -10 and GDF-5 and fibrillins, raising the possibility that latent TGFβ-binding proteins and fibrillins may mediate interactions with all other prodomains of this superfamily. This possibility is tested in this study. Results show that the prodomain of BMP-5 interacts with the N-terminal regions of fibrillin-1 and -2 in a site similar to the binding sites for other bone morphogenetic proteins. However, in contrast, the prodomain of GDF-8 (myostatin) interacts with the glycosaminoglycan side chains of perlecan. The binding site for the GDF-8 prodomain is likely the heparan sulfate chain present on perlecan domain V. These results support and extend the emerging concept that TGFβ superfamily prodomains target their growth factor dimers to extracellular matrix macromolecules. In addition, biochemical studies of prodomain·growth factor complexes were performed to identify inactive complexes. For some members of the superfamily, the prodomain is noncovalently associated with its growth factor dimer in an inactive complex; for others, the prodomain·growth factor complex is active, even though the prodomain is noncovalently associated with its growth factor dimer. Results show that the BMP-10 prodomain, in contrast to BMP-4, -5, and -7 prodomains, can inhibit the bioactivity of the BMP-10 growth factor and suggest that the BMP-10 complex is like TGFβ and GDF-8 complexes, which can be activated by cleavage of the associated prodomain.
影响因子：
2.9
作者：
GENTRY, LE;NASH, BW
通讯作者：
NASH, BW
影响因子：
5.6
作者：
Sengle, Gerhard;Ono, Robert N.;Lyons, Karen M.;Bachinger, Hans Peter;Sakai, Lynn Y.
通讯作者：
Sakai, Lynn Y.