A Structurally-Validated Multiple Sequence Alignment of 497 Human Protein Kinase Domains
A Structurally-Validated Multiple Sequence Alignment of 497 Human Protein Kinase Domains
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DOI：
10.1038/s41598-019-56499-4
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发表时间：
2019-12-24
影响因子：
4.6
通讯作者：
Dunbrack, Roland L., Jr.
中科院分区：
文献类型：
--
作者：
Modi, Vivek;Dunbrack, Roland L., Jr.
对单个激酶的结构和功能的研究已被用于了解尚未具有实验结构的其他激酶的生物学特性。通过同源性进行准确推断的关键因素是准确的序列比对。我们提出了一个简约的，基于结构的多序列比对（MSA）的497人蛋白激酶结构域不包括非典型激酶。比对排列在17个保守区域块和之间的未比对块中，所述未比对块包含仅存在于激酶子集中的不同长度的插入。对齐的块包含二级结构的高度保守的元件和众所周知的功能基序，如DFG和HRD基序。从272个人类激酶结构的成对、全对全比对中，我们估计MSA的准确性为97%。剩余的不准确性来自于二级结构中具有移位元件的少数结构，以及来自于对齐和未对齐区域的边界，其中需要做出妥协以涵盖大多数激酶。基于我们的比对，人类基因组中蛋白激酶结构域的一个新的同源性表明，先前标记为“其他”的10种激酶可以被确信地置于CAMK组中。这些激酶包括Aurora激酶、波罗激酶和钙/钙调蛋白依赖性激酶。
Studies on the structures and functions of individual kinases have been used to understand the biological properties of other kinases that do not yet have experimental structures. The key factor in accurate inference by homology is an accurate sequence alignment. We present a parsimonious, structure-based multiple sequence alignment (MSA) of 497 human protein kinase domains excluding atypical kinases. The alignment is arranged in 17 blocks of conserved regions and unaligned blocks in between that contain insertions of varying lengths present in only a subset of kinases. The aligned blocks contain well-conserved elements of secondary structure and well-known functional motifs, such as the DFG and HRD motifs. From pairwise, all-against-all alignment of 272 human kinase structures, we estimate the accuracy of our MSA to be 97%. The remaining inaccuracy comes from a few structures with shifted elements of secondary structure, and from the boundaries of aligned and unaligned regions, where compromises need to be made to encompass the majority of kinases. A new phylogeny of the protein kinase domains in the human genome based on our alignment indicates that ten kinases previously labeled as "OTHER" can be confidently placed into the CAMK group. These kinases comprise the Aurora kinases, Polo kinases, and calcium/calmodulin-dependent kinase kinases.