Nerve growth factor stimulates interaction of Cayman ataxia protein BNIP-H/Caytaxin with peptidyl-prolyl isomerase Pin1 in differentiating neurons.
Nerve growth factor stimulates interaction of Cayman ataxia protein BNIP-H/Caytaxin with peptidyl-prolyl isomerase Pin1 in differentiating neurons.
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DOI：
10.1371/journal.pone.0002686
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发表时间：
2008-07-16
期刊：
影响因子：
3.7
通讯作者：
Low BC
中科院分区：
文献类型：
--
作者：
Buschdorf JP;Chew LL;Soh UJ;Liou YC;Low BC
编码大脑特异蛋白BNIP-H(或Cayaxin)的ATCAY突变会导致开曼小脑性共济失调。BNIP-H与谷氨酰胺酶结合，谷氨酰胺酶是一种神经递质产生酶，影响其活性和细胞内定位。在这里，我们描述了BNIP-H与PIN1结合的鉴定和特征。PIN1是一种肽基-脯氨酰顺/反式异构酶。神经生长因子刺激后，BNIP-H与Pin1相互作用，并共同定位于分化中的嗜铬细胞瘤PC12细胞和胚胎癌细胞P19的突起和胞浆中。删除突变发现BNIP-H的C末端有两个隐蔽的结合位点，从而影响Pin1的WW结构域的单点突变完全取消了它们的结合。虽然这两个位点不包含任何典型的Pin1结合基序，但它们与Pin1 WW结构域突变体S16E、S16A和W34A及其异构酶结构域的催化惰性C113A显示出不同的结合图谱。此外，它们的直接相互作用只有在通过两个相似的区域破坏BNIP-H形成分子内相互作用的能力时才会发生。此外，在神经生长因子刺激下，Pin1的表达破坏了PC12细胞BNIP-H/谷氨酰胺酶复合体的形成。这些结果表明，神经生长因子可能通过释放BNIP-H与Pin1的分子内抑制来刺激BNIP-H与Pin1的相互作用。这种机制可以在神经元分化过程中对BNIP-H的细胞活性提供翻译后的调节。(213字)
Mutations in ATCAY that encodes the brain-specific protein BNIP-H (or Caytaxin) lead to Cayman cerebellar ataxia. BNIP-H binds to glutaminase, a neurotransmitter-producing enzyme, and affects its activity and intracellular localization. Here we describe the identification and characterization of the binding between BNIP-H and Pin1, a peptidyl-prolyl cis/trans isomerase. BNIP-H interacted with Pin1 after nerve growth factor-stimulation and they co-localized in the neurites and cytosol of differentiating pheochromocytoma PC12 cells and the embryonic carcinoma P19 cells. Deletional mutagenesis revealed two cryptic binding sites within the C-terminus of BNIP-H such that single point mutants affecting the WW domain of Pin1 completely abolished their binding. Although these two sites do not contain any of the canonical Pin1-binding motifs they showed differential binding profiles to Pin1 WW domain mutants S16E, S16A and W34A, and the catalytically inert C113A of its isomerase domain. Furthermore, their direct interaction would occur only upon disrupting the ability of BNIP-H to form an intramolecular interaction by two similar regions. Furthermore, expression of Pin1 disrupted the BNIP-H/glutaminase complex formation in PC12 cells under nerve growth factor-stimulation. These results indicate that nerve growth factor may stimulate the interaction of BNIP-H with Pin1 by releasing its intramolecular inhibition. Such a mechanism could provide a post-translational regulation on the cellular activity of BNIP-H during neuronal differentiation. (213 words)
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