Regulation of Kinase Activity in the Caenorhabditis elegans EGF Receptor, LET-23.
Regulation of Kinase Activity in the Caenorhabditis elegans EGF Receptor, LET-23.
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DOI：
10.1016/j.str.2017.12.012
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发表时间：
2018-02-06
期刊：
影响因子：
--
通讯作者：
Jura N
中科院分区：
文献类型：
--
作者：
Liu L;Thaker TM;Freed DM;Frazier N;Malhotra K;Lemmon MA;Jura N
在活性HER受体二聚体中，激酶发挥不同的作用;一种是催化活性激酶，另一种是其变构激活剂。这种特化使得能够通过无催化活性的HER 3进行信号传导，HER 3在与其他HER受体异源二聚化后仅作为变构激活剂发挥作用。目前还不清楚变构激活机制是否在HER受体功能特化之前进化。我们测定了C. elegans，LET-23.我们的非人EGFR激酶的结构揭示了在人对应物中保守的自抑制特征。引人注目的是，假定的变构二聚体界面内的突变消除了分离的LET-23激酶和全长受体的活性，尽管这些区域仅与人EGFR部分保守。我们的研究结果表明，祖先的EGFR具有内置的功能，使它们能够进行变构激活，这可能有助于催化死亡但功能正常的直系同源物的出现。Liu等提出了一种非人EGFR激酶C. elegans LET-23.他们的研究结果提供了对祖先EGFR调控的见解，表明LET-23通过寡聚化被变构激活，类似于人类EGFR，但通过一种可能在结构上不同的机制。
In the active HER receptor dimers, kinases play distinct roles; one is the catalytically active kinase and the other is its allosteric activator. This specialization enables signaling by the catalytically inactive HER3, which functions exclusively as an allosteric activator upon heterodimerization with other HER receptors. It is unclear whether the allosteric activation mechanism evolved before HER receptors functionally specialized. We determined the crystal structure of the kinase domain of the only EGF receptor in C. elegans, LET-23. Our structure of a non-human EGFR kinase reveals autoinhibitory features conserved in the human counterpart. Strikingly, mutations within the putative allosteric dimer interface abrogate activity of the isolated LET-23 kinase and of the full-length receptor despite these regions being only partially conserved with human EGFR. Our results indicate that ancestral EGFRs have built-in features that poise them for allosteric activation that could facilitate emergence of the catalytically dead, yet functional, orthologs. Liu et al. present the crystal structure of a non-human EGFR kinase, C. elegans LET-23. Their findings offer insights into the regulation of ancestral EGFRs, demonstrating that LET-23 is activated allosterically by oligomerization, similarly to human EGFR, but through a mechanism that is likely structurally distinct.
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影响因子：
16.6
作者：
Freed, Daniel M.;Alvarado, Diego;Lemmon, Mark A.
通讯作者：
Lemmon, Mark A.
影响因子：
5.7
作者：
Qiu, Chen;Tarrant, Mary K.;Leahy, Daniel J.
通讯作者：
Leahy, Daniel J.
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
影响因子：
6.5
作者：
Anisimova, Maria;Gascuel, Olivier
通讯作者：
Gascuel, Olivier