D-AKAP2:PKA RI 复合物的结构：对 AKAP 特异性和选择性的深入了解。
Structure of D-AKAP2:PKA RI complex: insights into AKAP specificity and selectivity.
机构信息
Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, MC 0654, La Jolla, CA 92093, USA.
出版信息
Structure. 2010 Feb 10;18(2):155-66. doi: 10.1016/j.str.2009.12.012.
Abstract
A-kinase anchoring proteins (AKAPs) regulate cyclic AMP-dependent protein kinase (PKA) signaling in space and time. Dual-specific AKAP 2 (D-AKAP2) binds to the dimerization/docking (D/D) domain of both RI and RII regulatory subunits of PKA with high affinity. Here we have determined the structures of the RIalpha D/D domain alone and in complex with D-AKAP2. The D/D domain presents an extensive surface for binding through a well-formed N-terminal helix, and this surface restricts the diversity of AKAPs that can interact. The structures also underscore the importance of a redox-sensitive disulfide in affecting AKAP binding. An unexpected shift in the helical register of D-AKAP2 compared to the RIIalpha:D-AKAP2 complex structure makes the mode of binding to RIalpha novel. Finally, the comparison allows us to deduce a molecular explanation for the sequence and spatial determinants of AKAP specificity.
摘要
蛋白激酶 A (PKA) 的锚定蛋白 (AKAPs) 在空间和时间上调节环腺苷酸依赖性蛋白激酶 (PKA) 信号。双特异性 AKAP2 (D-AKAP2) 以高亲和力结合 PKA 的 RI 和 RII 调节亚基的二聚体/对接 (D/D) 结构域。在此，我们确定了 RIalpha D/D 结构域及其与 D-AKAP2 复合物的结构。D/D 结构域通过一个形成良好的 N 端螺旋呈现出广泛的结合表面，该表面限制了可相互作用的 AKAP 的多样性。这些结构还强调了氧化还原敏感二硫键在影响 AKAP 结合中的重要性。与 RIIalpha:D-AKAP2 复合物结构相比，D-AKAP2 的螺旋登记的意外变化使得与 RIalpha 的结合方式具有新颖性。最后，这种比较使我们能够推断出 AKAP 特异性的序列和空间决定因素的分子解释。
相似文献
1
Structure of D-AKAP2:PKA RI complex: insights into AKAP specificity and selectivity.D-AKAP2:PKA RI 复合物的结构：对 AKAP 特异性和选择性的深入了解。
Structure. 2010 Feb 10;18(2):155-66. doi: 10.1016/j.str.2009.12.012.
2
D-AKAP2:PKA RII:PDZK1 ternary complex structure: insights from the nucleation of a polyvalent scaffold.D-AKAP2：蛋白激酶A RII：PDZK1三元复合物结构：来自多价支架成核的见解
Protein Sci. 2015 Jan;24(1):105-16. doi: 10.1002/pro.2593. Epub 2014 Dec 5.
3
Sphingosine kinase interacting protein is an A-kinase anchoring protein specific for type I cAMP-dependent protein kinase.鞘氨醇激酶相互作用蛋白是一种蛋白激酶 A 锚定蛋白，特异性结合 I 型环腺苷酸依赖的蛋白激酶。
Chembiochem. 2010 May 3;11(7):963-71. doi: 10.1002/cbic.201000058.
4
D-AKAP2, a novel protein kinase A anchoring protein with a putative RGS domain.D-AKAP2，一种具有假定RGS结构域的新型蛋白激酶A锚定蛋白。
Proc Natl Acad Sci U S A. 1997 Oct 14;94(21):11184-9. doi: 10.1073/pnas.94.21.11184.
5
PKA-type I selective constrained peptide disruptors of AKAP complexes.PKA-I型AKAP复合物的选择性受限肽干扰剂
ACS Chem Biol. 2015 Jun 19;10(6):1502-10. doi: 10.1021/acschembio.5b00009. Epub 2015 Mar 25.
6
A small novel A-kinase anchoring protein (AKAP) that localizes specifically protein kinase A-regulatory subunit I (PKA-RI) to the plasma membrane.一种小分子的蛋白激酶 A 锚定蛋白（AKAP），可将蛋白激酶 A 调节亚单位 I（PKA-RI）特异性地定位于质膜。
J Biol Chem. 2012 Dec 21;287(52):43789-97. doi: 10.1074/jbc.M112.395970. Epub 2012 Oct 31.
7
AKAP18:PKA-RIIα structure reveals crucial anchor points for recognition of regulatory subunits of PKA.AKAP18:PKA-RIIα结构揭示了识别蛋白激酶A调节亚基的关键锚定位点。
Biochem J. 2016 Jul 1;473(13):1881-94. doi: 10.1042/BCJ20160242. Epub 2016 Apr 21.
8
A dynamic mechanism for AKAP binding to RII isoforms of cAMP-dependent protein kinase.一种使A激酶锚定蛋白（AKAP）与环磷酸腺苷（cAMP）依赖性蛋白激酶的RII亚型结合的动态机制。
Mol Cell. 2006 Nov 3;24(3):397-408. doi: 10.1016/j.molcel.2006.09.015.
9
Distinct interaction modes of an AKAP bound to two regulatory subunit isoforms of protein kinase A revealed by amide hydrogen/deuterium exchange.通过酰胺氢/氘交换揭示的AKAP与蛋白激酶A的两种调节亚基异构体结合的不同相互作用模式。
Protein Sci. 2005 Dec;14(12):2982-92. doi: 10.1110/ps.051687305. Epub 2005 Oct 31.
10
A systematic evaluation of protein kinase A-A-kinase anchoring protein interaction motifs.蛋白激酶A - A激酶锚定蛋白相互作用基序的系统评估
Biochemistry. 2015 Jan 13;54(1):11-21. doi: 10.1021/bi500721a. Epub 2014 Sep 10.
引用本文的文献
1
Metabolic engineering of for the production of active hemoglobins and myoglobins by improving heme supply.通过改善血红素供应对用于生产活性血红蛋白和肌红蛋白进行代谢工程改造。
Proc Natl Acad Sci U S A. 2025 Jul 8;122(27):e2504795122. doi: 10.1073/pnas.2504795122. Epub 2025 Jul 2.
2
Aberrant phase separation of two PKA RIβ neurological disorder mutants leads to mechanistically distinct signaling deficits.两种蛋白激酶A RIβ神经障碍突变体的异常相分离导致机制上截然不同的信号缺陷。
Cell Rep. 2025 Jun 24;44(6):115797. doi: 10.1016/j.celrep.2025.115797. Epub 2025 Jun 11.
3
Redox Regulation of cAMP-Dependent Protein Kinase and Its Role in Health and Disease.环磷酸腺苷依赖性蛋白激酶的氧化还原调节及其在健康与疾病中的作用
Life (Basel). 2025 Apr 16;15(4):655. doi: 10.3390/life15040655.
4
Screening of novel β-carotene hydroxylases for the production of β-cryptoxanthin and zeaxanthin and the impact of enzyme localization and crowding on their production in Yarrowia lipolytica.筛选新型β-胡萝卜素羟化酶生产β-隐黄质和玉米黄质，以及酶定位和拥挤对其在解脂耶氏酵母中生产的影响。
Microb Cell Fact. 2024 Nov 5;23(1):298. doi: 10.1186/s12934-024-02569-w.
5
Identification of genetic association between mitochondrial dysfunction and knee osteoarthritis through integrating multi-omics: a summary data-based Mendelian randomization study.通过整合多组学技术识别线粒体功能障碍与膝骨关节炎的遗传关联：基于汇总数据的孟德尔随机化研究。
Clin Rheumatol. 2024 Nov;43(11):3487-3496. doi: 10.1007/s10067-024-07136-7. Epub 2024 Sep 11.
6
Molecular mechanism of IKK catalytic dimer docking to NF-κB substrates.IKK 催化二聚体与 NF-κB 底物对接的分子机制。
Nat Commun. 2024 Sep 3;15(1):7692. doi: 10.1038/s41467-024-52076-0.
7
Structural basis of binding the unique N-terminal domain of microtubule-associated protein 2c to proteins regulating kinases of signaling pathways.微管相关蛋白 2c 的独特 N 端结构域与调控信号通路激酶的蛋白质结合的结构基础。
J Biol Chem. 2024 Aug;300(8):107551. doi: 10.1016/j.jbc.2024.107551. Epub 2024 Jul 11.
8
Enhancing astaxanthin biosynthesis and pathway expansion towards glycosylated C40 carotenoids by Corynebacterium glutamicum.通过谷氨酸棒杆菌增强虾青素生物合成和途径扩展，生成糖基化 C40 类胡萝卜素。
Sci Rep. 2024 Apr 6;14(1):8081. doi: 10.1038/s41598-024-58700-9.
9
Molecular determinants and signaling effects of PKA RIα phase separation.PKA RIα 相分离的分子决定因素和信号效应。
Mol Cell. 2024 Apr 18;84(8):1570-1584.e7. doi: 10.1016/j.molcel.2024.03.002. Epub 2024 Mar 26.
10
The cAMP-PKA signalling crosstalks with CWI and HOG-MAPK pathways in yeast cell response to osmotic and thermal stress.在酵母细胞对渗透和热应激的反应中，cAMP-PKA信号通路与CWI和HOG-MAPK通路发生信号串扰。
Microb Cell. 2024 Mar 15;11:90-105. doi: 10.15698/mic2024.03.818. eCollection 2024.
本文引用的文献
1
Processing of X-ray diffraction data collected in oscillation mode.振荡模式下收集的X射线衍射数据的处理。
Methods Enzymol. 1997;276:307-26. doi: 10.1016/S0076-6879(97)76066-X.
2
Phaser crystallographic software.相位结晶学软件。
J Appl Crystallogr. 2007 Aug 1;40(Pt 4):658-674. doi: 10.1107/S0021889807021206. Epub 2007 Jul 13.
3
A short history of SHELX.SHELX简史。
Acta Crystallogr A. 2008 Jan;64(Pt 1):112-22. doi: 10.1107/S0108767307043930. Epub 2007 Dec 21.
4
PKA-I holoenzyme structure reveals a mechanism for cAMP-dependent activation.蛋白激酶A-I全酶结构揭示了一种cAMP依赖性激活的机制。
Cell. 2007 Sep 21;130(6):1032-43. doi: 10.1016/j.cell.2007.07.018.
5
Association of gene polymorphisms with myocardial infarction in individuals with different lipid profiles.不同血脂谱个体中基因多态性与心肌梗死的关联
Int J Mol Med. 2007 Oct;20(4):581-90.
6
Gene-trapped mouse embryonic stem cell-derived cardiac myocytes and human genetics implicate AKAP10 in heart rhythm regulation.基因捕获的小鼠胚胎干细胞衍生心肌细胞和人类遗传学研究表明AKAP10参与心律调节。
Proc Natl Acad Sci U S A. 2007 May 15;104(20):8461-6. doi: 10.1073/pnas.0610393104. Epub 2007 May 7.
7
8
A dynamic mechanism for AKAP binding to RII isoforms of cAMP-dependent protein kinase.一种使A激酶锚定蛋白（AKAP）与环磷酸腺苷（cAMP）依赖性蛋白激酶的RII亚型结合的动态机制。
Mol Cell. 2006 Nov 3;24(3):397-408. doi: 10.1016/j.molcel.2006.09.015.
9
Molecular basis of AKAP specificity for PKA regulatory subunits.A激酶锚定蛋白（AKAP）对蛋白激酶A（PKA）调节亚基特异性的分子基础。
Mol Cell. 2006 Nov 3;24(3):383-95. doi: 10.1016/j.molcel.2006.09.006.
10
The functional genetic variant Ile646Val located in the kinase binding domain of the A-kinase anchoring protein 10 is associated with familial breast cancer.位于A激酶锚定蛋白10激酶结合域的功能性基因变体Ile646Val与家族性乳腺癌相关。
Carcinogenesis. 2007 Feb;28(2):423-6. doi: 10.1093/carcin/bgl164. Epub 2006 Sep 6.
Zotero 插件