Emergence of protein fold families through rational design.
Emergence of protein fold families through rational design.
复制标题
DOI：
10.1371/journal.pcbi.0020085
复制
发表时间：
2006-07-07
影响因子：
4.3
通讯作者：
Dokholyan NV
中科院分区：
文献类型：
--
作者：
Ding F;Dokholyan NV
如果它们的序列相似性分别高于或低于20%-30%，则具有相似结构的不同蛋白质被归类为同系物和类似物家族。有人认为，蛋白质同源物和类似物起源于共同的祖先，在不同的进化时间尺度上存在分歧，是蛋白质序列空间物理性质的结果。虽然许多研究已经确定了蛋白质家族组织的关键特征，但区分这两个进化相关蛋白质家族的序列结构因素仍然未知。在这里，我们规定，由于同源家族中积累的突变而出现的细微结构变化，导致蛋白质核心的不同堆积，从而导致核心残基的新组成。后一个过程导致形成不同的同系物家族。我们认为，这种分化导致了相似家族的形成。为了测试我们的假设，我们开发了一个分子建模和设计工具包Medusa，用于计算设计对应于相同折叠家族的蛋白质序列。我们发现，当主干结构与原始结构的均方根偏差仅为1-2时，类似的蛋白质就会出现。对于紧密的同源基因，核心残基是高度保守的。然而，当总序列相似性下降到~25%-30%时，核心残基的组成开始分化，从而形成新的蛋白质同源物家族。这种对特定折叠家族内蛋白质同源物形成的直接观察支持了我们的假设。设计序列中氨基酸的保守性概括了自然发生的序列的保守性，从而验证了我们的计算设计方法。对已知蛋白质的研究揭示了它们的序列和结构有趣的共同组织。序列相似性高于25%-30%的蛋白质通常采用相似的结构，称为同源物，而序列相似性较低的蛋白质(<；20%)可以具有相同的结构，称为类似物。这种共同组织的起源一直是蛋白质折叠、设计和进化研究界广泛讨论的话题，因为理解蛋白质宇宙中同源和类似物的出现对于我们合理操作蛋白质的能力具有广泛的意义。在这项研究中，作者发展了一种分子建模和设计方法Medusa，用于计算设计与相似骨架结构相对应的各种蛋白质序列，从而确定蛋白质折叠家族。利用Medusa，作者直接证明了当结构与原始结构仅偏离1-2ä时，特定折叠家族内形成不同的蛋白质同源物。研究表明，由于同源物家族中积累的突变而出现的细微结构变化，导致蛋白质核心的不同堆积，从而导致核心残基的新组成。后一个过程导致形成不同的同系物家族。
Diverse proteins with similar structures are grouped into families of homologs and analogs, if their sequence similarity is higher or lower, respectively, than 20%–30%. It was suggested that protein homologs and analogs originate from a common ancestor and diverge in their distinct evolutionary time scales, emerging as a consequence of the physical properties of the protein sequence space. Although a number of studies have determined key signatures of protein family organization, the sequence-structure factors that differentiate the two evolution-related protein families remain unknown. Here, we stipulate that subtle structural changes, which appear due to accumulating mutations in the homologous families, lead to distinct packing of the protein core and, thus, novel compositions of core residues. The latter process leads to the formation of distinct families of homologs. We propose that such differentiation results in the formation of analogous families. To test our postulate, we developed a molecular modeling and design toolkit, Medusa, to computationally design protein sequences that correspond to the same fold family. We find that analogous proteins emerge when a backbone structure deviates only 1–2 Å root-mean-square deviation from the original structure. For close homologs, core residues are highly conserved. However, when the overall sequence similarity drops to ~25%–30%, the composition of core residues starts to diverge, thereby forming novel families of protein homologs. This direct observation of the formation of protein homologs within a specific fold family supports our hypothesis. The conservation of amino acids in designed sequences recapitulates that of the naturally occurring sequences, thereby validating our computational design methodology. Studies of known proteins have revealed intriguing co-organization of their sequences and structures. Proteins with sequence similarity higher than 25%–30% usually adopt a similar structure and are called homologs, whereas those with low sequence similarity (<20%) can share the same structure and are referred as analogs. The origin of such co-organization has been a topic of extensive discussions among protein folding, design, and evolution research communities, because understanding of the emergence of homologs and analogs in the protein universe has broad implications for our ability to rationally manipulate proteins. In this study, the authors developed a molecular modeling and design method, Medusa, to computationally design diversified protein sequences that correspond to similar backbone structures, which determine a protein fold family. Using Medusa, the authors directly demonstrated the formation of distinct protein homologs within a specific fold family when the structure deviates only 1–2 Å away from the original structure. The study suggests that subtle structural changes, which appear due to accumulating mutations in the families of homologs, lead to a distinct packing of the protein core and, thus, novel compositions of core residues. The latter process leads to the formation of distinct families of homologs.
登录
查看更多内容
影响因子：
5.6
作者：
HOBOHM, U;SANDER, C
通讯作者：
SANDER, C
影响因子：
--
作者：
Feng, SB;Kapoor, TM;Schreiber, SL
通讯作者：
Schreiber, SL
影响因子：
3.4
作者：
Ding, F;Dokholyan, NV;Shakhnovich, EI
通讯作者：
Shakhnovich, EI
影响因子：
56.9
作者：
Dahiyat, BI;Mayo, SL
通讯作者：
Mayo, SL
DOI：
10.1016/s1359-0278(98)00072-8
发表时间：
1998-01-01
期刊：
FOLDING & DESIGN
影响因子：
--
作者：
Dokholyan, NV;Buldyrev, SV;Shakhnovich, EI
通讯作者：
Shakhnovich, EI