Evolutionarily conserved structural and functional roles of the FYVE domain.
Evolutionarily conserved structural and functional roles of the FYVE domain.
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DOI：
10.1042/bss0740095
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发表时间：
2007-01
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影响因子：
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通讯作者：
Akira Hayakawa;Susan J. Hayes;Deborah M. Leonard;D. Lambright;S. Corvera
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作者：
Akira Hayakawa;Susan J. Hayes;Deborah M. Leonard;D. Lambright;S. Corvera
FYVE域是一个近似域。与磷酸肌肽PtdIns3P结合的80个氨基酸基元具有高特异性和亲和力。它存在于人类基因组中的38个预测基因产物中，但只存在于秀丽隐杆线虫和黑胃果蝇的12-13个基因产物中。其中8种基因在这三种生物中都是高度保守的，它们包含的蛋白质在任何物种中都没有被发现。其中之一WDFY2似乎在秀丽隐杆线虫的早期内吞作用中起重要作用，并在RNAi （RNA干扰）筛选中被发现。有趣的是，秀丽隐杆线虫和黑腹线虫的一些蛋白质含有fyve样结构域，但在进化过程中失去了这个结构域。其中之一是Rabatin-5的同源物，Rabatin-5是一种在哺乳动物细胞中结合Rab5和Rabex-5的蛋白质，Rabex-5是Rab5的鸟嘌呤核苷酸交换因子。因此，Rabatin-5同源物表明，连接PtdIns3P和Rab5激活的机制是在进化过程中发展起来的。在哺乳动物细胞中，这些机制在结合PtdIns3P和rabb gtpase的蛋白（如EEA1、rabensyn -5和Rabip4’）的存在中是明显的。尽管在体外与PtdIns3P结合的能力相当，但FYVE结构域在完整细胞中与核内体相互作用的能力变化很大。这种变化是由于不参与PtdIns3P头基识别的残基赋予FYVE结构域的三个不同性质：这些性质是：(i)寡聚化的倾向，（ii）插入膜双层的能力，以及（iii）与双层表面不同的静电相互作用。不同的结合特性可能调节了特定的FYVE结构域蛋白与早期内体相互作用的程度和持续时间，从而调节了它们的生物学功能。
The FYVE domain is an approx. 80 amino acid motif that binds to the phosphoinositide PtdIns3P with high specificity and affinity. It is present in 38 predicted gene products within the human genome, but only in 12-13 in Caenorhabditis elegans and Drosophila melanogaster. Eight of these are highly conserved in all three organisms, and they include proteins that have not been characterized in any species. One of these, WDFY2, appears to play an important role in early endocytosis and was revealed in a RNAi (RNA interference) screen in C. elegans. Interestingly, some proteins contain FYVE-like domains in C. elegans and D. melanogaster, but have lost this domain during evolution. One of these is the homologue of Rabatin-5, a protein that, in mammalian cells, binds both Rab5 and Rabex-5, a guanine-nucleotide exchange factor for Rab5. Thus the Rabatin-5 homologue suggests that mechanisms to link PtdIns3P and Rab5 activation developed in evolution. In mammalian cells, these mechanisms are apparent in the existence of proteins that bind PtdIns3P and Rab GTPases, such as EEA1, Rabenosyn-5 and Rabip4'. Despite the comparable ability to bind to PtdIns3P in vitro, FYVE domains display widely variable abilities to interact with endosomes in intact cells. This variation is due to three distinct properties of FYVE domains conferred by residues that are not involved in PtdIns3P head group recognition: These properties are: (i) the propensity to oligomerize, (ii) the ability to insert into the membrane bilayer, and (iii) differing electrostatic interactions with the bilayer surface. The different binding properties are likely to regulate the extent and duration of the interaction of specific FYVE domain-containing proteins with early endosomes, and thereby their biological function.