Binding of F-spondin to amyloid-β precursor protein:: A candidate amyloid-β precursor protein ligand that modulates amyloid-β precursor protein cleavage
Binding of F-spondin to amyloid-β precursor protein:: A candidate amyloid-β precursor protein ligand that modulates amyloid-β precursor protein cleavage
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DOI：
10.1073/pnas.0308655100
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发表时间：
2004-02-24
影响因子：
11.1
通讯作者：
Südhof, TC
中科院分区：
文献类型：
--
作者：
Ho, A;Südhof, TC
淀粉样β前体蛋白（APP）是一种I型膜蛋白，由α-或β-分泌酶进行生理加工，分泌酶将APP N-末端切割至跨膜区。APP的细胞外α-/β-切割产生大的分泌的N-末端片段和较小的细胞C-末端片段。随后在C-末端片段的跨膜区中的γ-分泌酶切割诱导小的胞外肽的分泌，包括在阿尔茨海默病的发病机制中起作用的Abeta（40）和Abeta（42），以及胞质尾片段的胞内释放。虽然APP类似于细胞表面受体，但没有功能活性的APP胞外配体可以调节其蛋白水解过程。我们现在发现，F-spondin，一个分泌的信号分子参与神经元的发育和修复，结合到APP的保守的中央胞外结构域和抑制β-分泌酶切割的APP。我们的数据表明，F-spondin可能是一个内源性调节APP切割，并建议APP的胞外结构域是潜在的药物靶点干扰β-分泌酶切割。
Amyloid-beta precursor protein (APP), a type I membrane protein, is physiologically processed by alpha- or beta-secretases that cleave APP N-terminal to the transmembrane region. Extracellular alpha-/beta-cleavage of APP generates a large secreted N-terminal fragment, and a smaller cellular C-terminal fragment. Subsequent gamma-secretase cleavage in the transmembrane region of the C-terminal fragment induces secretion of small extracellular peptides, including Abeta(40) and Abeta(42), which are instrumental in the pathogenesis of Alzheimer's disease, and intracellular release of a cytoplasmic tail fragment. Although APP resembles a cell-surface receptor, no functionally active extracellular ligand for APP that might regulate its proteolytic processing has been described. We now show that F-spondin, a secreted signaling molecule implicated in neuronal development and repair, binds to the conserved central extracellular domain of APP and inhibits beta-secretase cleavage of APP. Our data indicate that F-spondin may be an endogenous regulator of APP cleavage, and suggest that the extracellular domains of APP are potential drug targets for interfering with beta-secretase cleavage.