CAMK2D

更新于：2025-05-07

基本信息

别名

calcium/calmodulin dependent protein kinase II delta、calcium/calmodulin-dependent protein kinase (CaM kinase) II delta、Calcium/calmodulin-dependent protein kinase type II subunit delta

+ [4]

简介

Calcium/calmodulin-dependent protein kinase involved in the regulation of Ca(2+) homeostatis and excitation-contraction coupling (ECC) in heart by targeting ion channels, transporters and accessory proteins involved in Ca(2+) influx into the myocyte, Ca(2+) release from the sarcoplasmic reticulum (SR), SR Ca(2+) uptake and Na(+) and K(+) channel transport. Targets also transcription factors and signaling molecules to regulate heart function. In its activated form, is involved in the pathogenesis of dilated cardiomyopathy and heart failure. Contributes to cardiac decompensation and heart failure by regulating SR Ca(2+) release via direct phosphorylation of RYR2 Ca(2+) channel on 'Ser-2808'. In the nucleus, phosphorylates the MEF2 repressor HDAC4, promoting its nuclear export and binding to 14-3-3 protein, and expression of MEF2 and genes involved in the hypertrophic program (PubMed:17179159). Is essential for left ventricular remodeling responses to myocardial infarction. In pathological myocardial remodeling acts downstream of the beta adrenergic receptor signaling cascade to regulate key proteins involved in ECC. Regulates Ca(2+) influx to myocytes by binding and phosphorylating the L-type Ca(2+) channel subunit beta-2 CACNB2. In addition to Ca(2+) channels, can target and regulate the cardiac sarcolemmal Na(+) channel Nav1.5/SCN5A and the K+ channel Kv4.3/KCND3, which contribute to arrhythmogenesis in heart failure. Phosphorylates phospholamban (PLN/PLB), an endogenous inhibitor of SERCA2A/ATP2A2, contributing to the enhancement of SR Ca(2+) uptake that may be important in frequency-dependent acceleration of relaxation (FDAR) and maintenance of contractile function during acidosis (PubMed:16690701). May participate in the modulation of skeletal muscle function in response to exercise, by regulating SR Ca(2+) transport through phosphorylation of PLN/PLB and triadin, a ryanodine receptor-coupling factor. In response to interferon-gamma (IFN-gamma) stimulation, catalyzes phosphorylation of STAT1, stimulating the JAK-STAT signaling pathway (By similarity).

关联

项与 CAMK2D 相关的药物

tat-CN19o

靶点

CAMK2B x CAMK2D x CaMKII

作用机制

CAMK2B抑制剂 [+2]

在研机构

The University of Colorado [+1]

原研机构

The University of Colorado

在研适应症

心脏停搏 [+1]

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 CAMK2D 相关的临床结果

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100 项与 CAMK2D 相关的转化医学

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0 项与 CAMK2D 相关的专利（医药）

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182

项与 CAMK2D 相关的文献（医药）

2025-03-01·Biochemical and Biophysical Research Communications

Discovery of myeloid zinc finger (MZF) 1 nuclear bodies

Article

作者: Calderwood, Stuart K ; Eguchi, Takanori

Myeloid zinc finger 1 (MZF1) is a multifaceted transcription factor that can act either as a transcriptional activator or a gene repressor. We examined its production of nuclear bodies (NBs) and subcellular localization. Proteomic and protein-protein interaction analysis were used to identify its cofactors and interactions. These revealed the presence of MZF1-NBs (intranuclear oligomers containing MZF1). MZF-NBs are similar to some other nuclear bodies, notably promyelocytic leukemia (PML) -NBs in terms of size and morphology. However the two structures appear to be different. MZF-NBs and PML-NBs were found to associate in the nucleus. Both MZF1 and PML are SUMO1-SUMOylated in PC-3 cells. Sumoylated MZF1 can interact with proteins containing SUMO-interaction motifs (SIM) through SUMO-SIM interaction. Interactome analysis revealed that its NBs participate in the stress response (TPR and UBAP2L), protein folding (CALR and ANKRD40), transcription, post-translational modification (TRIM33, ACOT7, CAMK2D, and CAMK2G), and RNA binding (ALURBP and CPSF5).

2025-03-01·Advanced Science

CAMKIIδ Reinforces Lipid Metabolism and Promotes the Development of B Cell Lymphoma

Article

作者: Liu, Xiaoqian ; Xu, Senlin ; Li, Ling ; Fang, Hui ; Feng, Mingye ; Huang, Wendong ; Shi, Yunfei ; Zhang, Mingfeng ; Gan, Yichao ; Zhong, Yaoyao ; Zhang, Shize ; Horne, David ; Hu, Zhenkang ; Wu, Dehao ; Yin, Jie ; Zhang, Jiawei ; Li, Yuan ; Tang, Mengyue ; Chan, Wing C ; Zhao, Junwei ; Gu, Ying ; Ouyang, Ching ; Wang, Yingda

AbstractThe most prevalent types of lymphomas are B cell lymphomas (BCL). Newer therapies for BCL have improved the prognosis for many patients. However, approximately 30% with aggressive BCL either remain refractory or ultimately relapse. These patients urgently need other options. This study shows how calcium/calmodulin‐dependent protein kinase II delta (CAMKIIδ) is pivotal for BCL development. In BCL cells, ablation of CAMKIIδ inhibits both lipolysis from lipid droplets and oxidative phosphorylation (OXPHOS). With lipolysis blocked, BCL progression is markedly suppressed in two distinct BCL mouse models: MYC‐driven EµMyc mice and Myc/Bcl2 double‐expressed mice. When CAMKIIδ is present, it destabilizes transcription factor Forkhead Box O3A (FOXO3A) by phosphorylating it at Ser7 and Ser12. This then permits transcription of downstream gene IRF4 – a master transcription factor of lipid metabolism. The CAMKIIδ/FOXO3A axis bolsters lipid metabolism, mitochondrial respiration, and tumor fitness in BCL under metabolic stress. This study also evaluates Tetrandrine (TET), a small molecule compound, as a potent CAMKIIδ inhibitor. TET attenuates metabolic fitness and elicits therapeutic responses both in vitro and in vivo. Collectively, this study highlights how CAMKIIδ is critical in BCL progression. The results also pave the way for innovative therapeutic strategies for treating aggressive BCL.

2025-01-28·Investigative Ophthalmology & Visual Science

CAMK2D and Complement Factor I–Involved Calcium/Calmodulin Signaling Modulates Sodium Iodate-Induced Mouse Retinal Degeneration

Article

作者: Liu, Hua ; Xu, Weixing ; Cao, Liu

PurposeTo investigate the effect of Ca2+/calmodulin-dependent protein kinase II (CAMKII) δ subtypes (CAMK2D) on sodium iodate (NaIO3)-induced retinal degeneration in mice.MethodsBioinformatics analysis and Western blot experiments were used to screen the significantly differentially expressed genes in age-related macular degeneration (AMD) disease. CAMK2D knockdown and overexpression models were constructed by lentivirus (LV) infection of adult retinal pigment epithelial cell line-19 (ARPE-19) cells in vitro. Flow cytometry was used to detect ARPE-19 cell apoptosis induced by NaIO3. In vivo, CAMK2D knockdown and overexpression mouse models were generated by infecting mouse retinal pigment epithelium (RPE) with adeno-associated virus (AAV). Retinography, optical coherence tomography (OCT), and histological analysis (hematoxylin and eosin staining) were used to detect NaIO3-induced retinal structural changes in mice. Electroretinography (ERG) was used to detect NaIO3-induced retinal function changes in mice. TdT-mediated dUTP nick-end labeling (TUNEL) staining was used to detect the apoptosis of retinal cells induced by NaIO3. RNA sequencing (RNA-Seq) and bioinformatics analysis were used to screen for target genes affected by CAMK2D in CAMK2D-overexpressing ARPE-19 cells. And flow cytometry, OCT, and ERG were used to evaluate the regulatory effect of CAMK2D on target genes.ResultsBioinformatics analysis found the expression of genes related to Ca2+ signal was significantly reduced in AMD patients. Western blot showed that in a mouse model of dry AMD induced by NaIO3, CAMK2D expression in RPE-Choroid tissue significantly lower than normal mice. In vitro, our results showed that overexpression of CAMK2D in ARPE-19 cells decreased apoptosis induced by NaIO3 and knockdown increased apoptosis. In vivo, CAMK2D overexpression in RPE cells can attenuate the retina degeneration induced by NaIO3 and CAMK2D knockdown aggravated degeneration. The bioinformatics analysis indicated that CAMK2D might affect AMD pathology through complement factor I (CFI). In vitro, knockdown of CFI in ARPE-19 cells increased apoptosis induced by NaIO3. In knockdown CFI ARPE-19 cells, overexpression of CAMK2D reduced the above apoptosis. In mice retina, CFI knockdown can aggravate the retina degeneration induced by NaIO3. In knockdown CFI mice, overexpression of CAMK2D in RPE can attenuate the above retina degeneration. Western blot confirmed that CAMK2D regulated the expression of CFI in mice.ConclusionsCAMK2D can attenuate the retinal degeneration induced by NaIO3, which was achieved by regulating the CFI.

项与 CAMK2D 相关的新闻（医药）

2024-11-22

·GoDesign

【分子设计】分子胶如何快人一步——探索CRBN底物组（上）

Monte Rosa Therapeutics是一家专注于分子胶降解剂（Molecular glue degrader，MGD）开发的公司，其研发管线聚焦于难成药靶点（GSPT1、VAV1、NEK7）。今年10月，Monte Rosa在BioRxiv上发表了其最新文章“Mining the CRBN Target Space Redefines Rules for Molecular Glue-induced Neosubstrate Recognition”，阐述了他们分子胶降解剂的开发历程。 ——背景—— 分子胶降解剂是一种利用细胞内蛋白质降解机制（如泛素-蛋白酶体、溶酶体等）来降解靶标蛋白的分子。目前研究最为深入的分子胶降解剂是以E3泛素连接酶CRBN为基础的分子胶降解剂，这类药物也被称为CRBN调节药物（Cereblon modulating drugs，CELMoDs）。CELMoD与CRBN结合，形成新的二元复合物界面，通过该界面招募新的底物（Neo-substrate）。已知的Neo-substrate有CK1α、GSPT1、IKZF1、IKZF2、WIZ等，这些都是传统意义上的难成药靶蛋白。这些Neo-substrate通过一个G-loop与CRBN/CELMoD结合，G-loop由β-hairpin α-turn构成，在特定位置有一个共同的甘氨酸，因此也被称为β-hairpin G-loop。目前已知数千种人类蛋白都包含这样的结构。鉴于三元复合物界面的简洁性，作者们试图回答两个问题：是否有更多的G-loop蛋白可被CELMoD诱导降解；除了G-loop，CRBN是否还能与其他结构兼容？ ——CRBN靶蛋白空间探索—— 计算挖掘：作者以CK1α的β-hairpin G-loop为查询模板（该模板由I35到E42八个氨基酸组成，包含5个上游残基（G-5）和2个下游残基（G+2）），在蛋白质结构数据库（PDB）和AlphaFold2（AF2）预测的人类蛋白质中进行搜索，选择与查询模板的均方根偏差（RMSD）小于0.75Å且与CRBN无空间位阻基序，并去除其中主要定位于细胞外的蛋白质，最终确定了1424种含有CRBN兼容β-hairpin G-loop的蛋白质，其中成功召回了含有已知β-hairpin G-loop底物（图1）。图1.A.G-loop模板C.可能与CRBN兼容的G-loop蛋白实验验证：作者在CAL51细胞中表达TurboID-CRBN，并提前加入CELMoDs，使与CRBN邻近的蛋白质发生生物素化，亲和纯化后进行质谱分析。以DMSO处理的对照细胞为参考，作者检测了化合物处理后蛋白质的富集情况，发现多种蛋白质在化合物存在下发生富集，包括已知的G-loop蛋白（CK1α,WEE1，GSPT1）和新发现的G-loop蛋白（NEK7、MNAT1、PPIL4和CHD7）（图2）。图2.TurboID实验结果 NanoBRET和TR-FRET实验验证：之后作者将关注点置于蛋白激酶上，这些激酶的N-lobe具备与CK1α同源的G-loop。作者选取了在TurboID实验中呈阳性的激酶（CK1α、WEE1、NEK7、SCYL1）以及其他一些激酶（CAMK2D、CK1δ、LIMK1、PLK3、STK4、TRIB1、TRIB3），通过NanoBRET和TR-FRET实验，最终确定了9种激酶（CK1α、WEE1、NEK7、SCYL1、CK1δ、LIMK1、PLK3、TRIB1、TRIB3）能够在CELMoDs存在下与CRBN形成三元复合物。此外，当把G-loop上的甘氨酸突变为天冬酰胺后，NanoBRET信号消失，这充分表明了G-loop在三元复合物形成过程中的关键作用。接着，作者进一步将研究范围拓展至先前未曾探索的结构域（RRM、WW、BRK、LIM-ZF、RINGZF、kinesin和HUP结构域），从中挑选出部分蛋白进行NanoBRET实验，以验证其与CRBN/CELMoD三元复合物的形成状况，确定了8种非激酶蛋白（如PPIL4、MNAT1、WBP4、LIMD1、CHD7、ASS1、HNRNPD、KIFC3等）能够与CRBN形成三元复合物（图3）。图3.NanoBRET实验结果小结：作者借助计算手段在人类蛋白质组中挖掘出与CRBN结合相关的β-hairpin G-loop，确定了1424种含有CRBN兼容β-hairpin G-loop的蛋白质，它们分布于多种蛋白质类别和结构域类型之中，其中一大类是已知的C₂H₂锌指蛋白。通过邻近连接实验（Turbo-ID）、NanoBRET和TR-FRET等实验，验证了多种新型β-hairpin G-loop蛋白与CRBN的相互作用，证实了G-loop基序的序列多样性，明确了不同的G环靶标需要不同的化学物质来与CRBN结合。 ——helical G-loop motifs的发现—— 通过对CK1α-Lenalidomide-CRBN三元复合物进行分析，作者确定G-loop参与蛋白-蛋白相互作用贡献最大的5个残基（G-3、G-2、G-1、G和G+1），以此为依据重新定义G-loop并进行挖掘，采用RMSD截止值为0.5Å，排除与CRBN空间位阻不兼容以及位于细胞外结构域的基序，从而得到1633种预测的G-loop蛋白，其中包含184种含有helical G-loop的蛋白质（图4）。图4.helicalG-loop蛋白 NanoBRET实验：作者针对预测含有helical G-loop的mTOR-FRB结构域开展NanoBRET实验，验证了其与CRBN和化合物Cpd.1的三元复合物形成情况。在突变甘氨酸残基G2092后检测信号变化，证实了mTOR-FRB helical G-loop作为CRBN识别基序的作用；对预测含有helical G-loop的酪氨酸激酶LCK、HCK和LYN（其helical G-loop位于激酶C-lobe的αEF螺旋远端）进行NanoBRET实验，观察到这三种激酶可被不同的小分子诱导，与CRBN形成三元复合物，并且突变G-loop甘氨酸残基能够消除三元复合物的形成，从而验证了预测结果（图5）。图5.激酶与CRBN的邻近晶体结构测定：作者解析了DDB1ΔB-CRBNΔ1-40、Cpd.1和mTOR-FRB2022-2114三元复合物的晶体结构（2.95Å），揭示了helical G-loop在复合物中的作用机制，即helical G-loop在mTOR-FRB的四螺旋束顶端通过其C末端CULT结构域与CRBN相互作用，形成与β-hairpin G-loop相似的主链相互作用，且由于螺旋折叠的变化，其G-4残基的主链几何形状与β-hairpin G-loop不同，导致化合物界面更紧凑。小结：作者发现了一种新的helical G-loop基序，存在于184种蛋白质中，扩展了CRBN-neosubstrate的范围，超越了β-hairpin G-loop。通过生物信息学预测和实验验证，确定了1633种蛋白质原则上可通过G-loop基序被分子胶降解剂（MGD）诱导招募至CRBN，其中1424种含有β-hairpin G-loop，184种含有helical G-loop。mTOR-FRB结构域中的helical G-loop通过C末端CULT结构域与CRBN/CELMoD相互作用形成三元复合物，其招募依赖于甘氨酸残基G2092；酪氨酸激酶LCK、HCK和LYN也可与CRBN/CELMoD相互作用。参考文献： [1] Petzold, G.; Gainza, P.; Annunziato, S.; Lamberto, I.; Trenh, P.; McAllister, L.; Demarco, B.; Schwander, L.; Bunker, R. D.; Zlotosch, M.; et al. Mining the CRBN Target Space Redefines Rules for Molecular Glue-induced Neosubstrate Recognition. bioRxiv 2024, 2024.2010.2007.616933. DOI: 10.1101/2024.10.07.616933. 作者：任宇浩审稿：郭政编辑：郭政 GoDesign ID：Molecular_Design_Lab （扫描下方二维码可以订阅哦！）点击阅读原文即可查看文献链接 Andy M. Lau et al.

细胞疗法临床结果