Department of Biochemistry and Molecular Biology, University of Georgia, Athens, Georgia, United States of America.
PLoS One. 2010 Dec 13;5(12):e14310. doi: 10.1371/journal.pone.0014310.
The epidermal growth factor receptor kinases, or ErbB kinases, belong to a large sub-group of receptor tyrosine kinases (RTKs), which share a conserved catalytic core. The catalytic core of ErbB kinases have functionally diverged from other RTKs in that they are activated by a unique allosteric mechanism that involves specific interactions between the kinase core and the flanking Juxtamembrane (JM) and COOH-terminal tail (C-terminal tail). Although extensive studies on ErbB and related tyrosine kinases have provided important insights into the structural basis for ErbB kinase functional divergence, the sequence features that contribute to the unique regulation of ErbB kinases have not been systematically explored.
METHODOLOGY/PRINCIPAL FINDINGS: In this study, we use a Bayesian approach to identify the selective sequence constraints that most distinguish ErbB kinases from other receptor tyrosine kinases. We find that strong ErbB kinase-specific constraints are imposed on residues that tether the JM and C-terminal tail to key functional regions of the kinase core. A conserved RIxKExE motif in the JM-kinase linker region and a glutamine in the inter-lobe linker are identified as two of the most distinguishing features of the ErbB family. While the RIxKExE motif tethers the C-terminal tail to the N-lobe of the kinase domain, the glutamine tethers the C-terminal tail to hinge regions critical for inter-lobe movement. Comparison of the active and inactive crystal structures of ErbB kinases indicates that the identified residues are conformationally malleable and can potentially contribute to the cis regulation of the kinase core by the JM and C-terminal tail. ErbB3, and EGFR orthologs in sponges and parasitic worms, diverge from some of the canonical ErbB features, providing insights into sub-family and lineage-specific functional specialization.
CONCLUSION/SIGNIFICANCE: Our analysis pinpoints key residues for mutational analysis, and provides new clues to cancer mutations that alter the canonical modes of ErbB kinase regulation.
表皮生长因子受体激酶（ErbB 激酶）属于受体酪氨酸激酶（RTK）的一个大亚群，它们具有保守的催化核心。ErbB 激酶的催化核心在功能上已经与其他 RTK 分化，因为它们的激活是通过一种独特的变构机制实现的，这种机制涉及激酶核心与侧翼的跨膜区（JM）和羧基末端尾部（C 末端尾部）之间的特定相互作用。尽管对 ErbB 和相关酪氨酸激酶的广泛研究为 ErbB 激酶功能分化的结构基础提供了重要的见解，但导致 ErbB 激酶独特调节的序列特征尚未得到系统探索。
方法/主要发现：在这项研究中，我们使用贝叶斯方法来识别最能区分 ErbB 激酶与其他受体酪氨酸激酶的选择性序列约束。我们发现，将 JM 和 C 末端尾部固定在激酶核心关键功能区域的残基上，对 ErbB 激酶施加了强烈的特异性约束。在 JM-激酶连接区域中保守的 RIxKExE 基序和在间叶连接区中的谷氨酰胺被确定为 ErbB 家族的两个最具区分特征。虽然 RIxKExE 基序将 C 末端尾部固定在激酶结构域的 N lobe 上，但谷氨酰胺将 C 末端尾部固定在对于间叶运动至关重要的铰链区域。比较 ErbB 激酶的活性和非活性晶体结构表明，鉴定的残基具有构象可塑性，并且可以潜在地有助于 JM 和 C 末端尾部对激酶核心的顺式调节。海绵和寄生蠕虫中的 ErbB3 和 EGFR 同源物与一些典型的 ErbB 特征不同，为亚家族和谱系特异性功能专业化提供了新的见解。
结论/意义：我们的分析确定了突变分析的关键残基，并为改变 ErbB 激酶调节的典型模式的癌症突变提供了新的线索。
