Prodomains regulate the synthesis, extracellular localisation and activity of TGF-β superfamily ligands
Prodomains regulate the synthesis, extracellular localisation and activity of TGF-β superfamily ligands
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DOI：
10.3109/08977194.2011.608666
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发表时间：
2011-10-01
期刊：
影响因子：
1.8
通讯作者：
Walton, Kelly L.
中科院分区：
文献类型：
--
作者：
Harrison, Craig A.;Al-Musawi, Sara L.;Walton, Kelly L.
所有转化生长因子-β（TGF-β）配体都是作为前体分子合成的，由信号肽、N-末端前结构域和C-末端成熟结构域组成。在合成过程中，前结构域与成熟结构域非共价相互作用，使分子保持在适合二聚化的构象。二聚体前体被前蛋白转化酶切割，并且TGF-β配体从细胞分泌，与它们的前结构域非共价结合。在细胞外，前结构域通过与细胞外基质蛋白（包括原纤维蛋白和串珠素）的相互作用将TGF-β配体定位在其靶细胞附近。对于某些家族成员（TGF-β 1、TGF-β 2、TGF-β 3、肌生长抑制素、GDF-11和BMP-10），前结构域以足够高的亲和力结合以抑制生物活性。这些潜在TGF-β配体的后续活化机制根据细胞类型和环境而变化，但所有活化机制都直接靶向前结构域。因此，前结构域控制TGF-β超家族生物学的许多方面，并且前结构域功能的改变通常与疾病相关。
All transforming growth factor-beta (TGF-beta) ligands are synthesised as precursor molecules consisting of a signal peptide, an N-terminal prodomain and a C-terminal mature domain. During synthesis, prodomains interact non-covalently with mature domains, maintaining the molecules in a conformation competent for dimerisation. Dimeric precursors are cleaved by proprotein convertases, and TGF-beta ligands are secreted from the cell non-covalently associated with their prodomains. Extracellularly, prodomains localise TGF-beta ligands within the vicinity of their target cells via interactions with extracellular matrix proteins, including fibrillin and perlecan. For some family members (TGF-beta 1, TGF-beta 2, TGF-beta 3, myostatin, GDF-11 and BMP-10), prodomains bind with high enough affinity to suppress biological activity. The subsequent mechanism of activation of these latent TGF-beta ligands varies according to cell type and context, but all activating mechanisms directly target prodomains. Thus, prodomains control many aspects of TGF-beta superfamily biology, and alterations in prodomain function are often associated with disease.