The origins of specificity in polyketide synthase protein interactions.
The origins of specificity in polyketide synthase protein interactions.
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DOI：
10.1371/journal.pcbi.0030186
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发表时间：
2007-09
影响因子：
4.3
通讯作者：
Shraiman BI
中科院分区：
文献类型：
--
作者：
Thattai M;Burak Y;Shraiman BI
聚酮是一种具有抗生素和抗肿瘤特性的异聚物，是由模块化聚酮合成酶（PKS）蛋白的多蛋白链在细菌中组装而成的。特定的蛋白质-蛋白质相互作用决定了多蛋白质链中蛋白质的顺序，从而决定了化学上不同的单体被添加到生长中的聚酮产物中的顺序。在这里，我们研究了蛋白质相互作用特异性的进化和分子起源。我们专注于短的，保守的N端和c端对接域，它们介导模块化PKS蛋白之间的相互作用。我们的计算分析结合了蛋白质序列数据和实验蛋白质相互作用数据，揭示了一个分层相互作用特异性代码。PKS对接结构域起源于一个单一的祖先相互作用对，但已经分裂成三个相互不相互作用的系统发育类。一个这样的相容性类中的特异性是由几个关键残基决定的，这些残基可以用来定义相容性子类。我们使用一种新的、高度敏感的协同进化检测算法来识别这些残基，这种算法称为CRoSS（统计显著性相关残基）。CRoSS选择的残基对在停靠域核磁共振结构中参与直接的物理相互作用。单个PKS系统可以使用来自多个类的对接域对，也可以使用来自任何给定类的多个子类的对接域对。单个蛋白质的末端经常被洗刷，但跨越两个相互作用蛋白质的对接结构域对作为一个进化模块连接在一起。特异性编码的分层和模块化组织与细菌产生新的PKS途径的过程密切相关。生物分子间的相互作用是非常特殊的。在许多情况下，蛋白质可以从大量密切相关的候选分子中选择其唯一正确的结合伙伴。对于聚酮合成酶（pks），一个细菌酶家族，这种特异性是必不可少的。就像流水线上的工人一样，PKSs的功能是多蛋白链，每一种酶在将其传递给下一种酶之前都会修饰它的底物。就像一个精心设计的拼图游戏，整个多蛋白链被正确地精确排序，因为每个组成蛋白只能与特定的最近的邻居结合。PKS多蛋白链是由每个蛋白质两端的粘性“头”和“尾”结构域连接在一起的，一个蛋白质的头部与另一个蛋白质的尾部结合。我们在这些结构域的氨基酸序列中寻找模式，以解释为什么某些正反成对结合，而另一些则不结合。我们发现正面和反面都有三种不同的变体。不匹配的头尾对根本不结合，而匹配的头尾对的结合是由这些结构域之间物理界面上几个关键位置的氨基酸控制的。
Polyketides, a diverse group of heteropolymers with antibiotic and antitumor properties, are assembled in bacteria by multiprotein chains of modular polyketide synthase (PKS) proteins. Specific protein–protein interactions determine the order of proteins within a multiprotein chain, and thereby the order in which chemically distinct monomers are added to the growing polyketide product. Here we investigate the evolutionary and molecular origins of protein interaction specificity. We focus on the short, conserved N- and C-terminal docking domains that mediate interactions between modular PKS proteins. Our computational analysis, which combines protein sequence data with experimental protein interaction data, reveals a hierarchical interaction specificity code. PKS docking domains are descended from a single ancestral interacting pair, but have split into three phylogenetic classes that are mutually noninteracting. Specificity within one such compatibility class is determined by a few key residues, which can be used to define compatibility subclasses. We identify these residues using a novel, highly sensitive co-evolution detection algorithm called CRoSS (correlated residues of statistical significance). The residue pairs selected by CRoSS are involved in direct physical interactions in a docked-domain NMR structure. A single PKS system can use docking domain pairs from multiple classes, as well as domain pairs from multiple subclasses of any given class. The termini of individual proteins are frequently shuffled, but docking domain pairs straddling two interacting proteins are linked as an evolutionary module. The hierarchical and modular organization of the specificity code is intimately related to the processes by which bacteria generate new PKS pathways. Biomolecular interactions can be extraordinarily specific. In many instances, a protein can select its single correct binding partner from among a large array of closely related candidates. For polyketide synthases (PKSs), a family of bacterial enzymes, such specificity is essential. Like workers on an assembly line, PKSs function as multiprotein chains, each enzyme modifying its substrate before passing it along to the next. And like a well-designed jigsaw puzzle, the overall multiprotein chain is correctly ordered precisely because each component protein can only bind to specific nearest neighbors. A PKS multiprotein chain is held together by sticky “head” and “tail” domains found at either end of each protein, the head of one protein binding to the tail of the next. We looked for patterns in the amino-acid sequences of these domains that could explain why certain head–tail pairs bind, while others do not. We discovered that heads and tails each come in three very different varieties. Mismatched head–tail pairs do not bind at all, while the binding of a matching head–tail pair is governed by the amino acids found at a few key positions on the physical interface between these domains.
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影响因子：
14.9
作者：
Ansari, MZ;Yadav, G;Mohanty, D
通讯作者：
Mohanty, D
DOI：
10.1038/nsb881
发表时间：
2003-01-01
期刊：
NATURE STRUCTURAL BIOLOGY
影响因子：
--
作者：
Süel, GM;Lockless, SW;Ranganathan, R
通讯作者：
Ranganathan, R
影响因子：
2.9
作者：
Wu, N;Cane, DE;Khosla, C
通讯作者：
Khosla, C
影响因子：
56.9
作者：
Gokhale, RS;Tsuji, SY;Khosla, C
通讯作者：
Khosla, C
影响因子：
2.9
作者：
Kim, BS;Cropp, TA;Reynolds, KA
通讯作者：
Reynolds, KA