An Activity-Guided Map of Electrophile-Cysteine Interactions in Primary Human T Cells.
An Activity-Guided Map of Electrophile-Cysteine Interactions in Primary Human T Cells.
复制标题
DOI：
10.1016/j.cell.2020.07.001
复制
发表时间：
2020-08-20
期刊：
影响因子：
64.5
通讯作者：
Cravatt BF
中科院分区：
文献类型：
--
作者：
Vinogradova EV;Zhang X;Remillard D;Lazar DC;Suciu RM;Wang Y;Bianco G;Yamashita Y;Crowley VM;Schafroth MA;Yokoyama M;Konrad DB;Lum KM;Simon GM;Kemper EK;Lazear MR;Yin S;Blewett MM;Dix MM;Nguyen N;Shokhirev MN;Chin EN;Lairson LL;Melillo B;Schreiber SL;Forli S;Teijaro JR;Cravatt BF
来源于自然或化学合成的亲电化合物对免疫细胞有深远的影响。这些化合物被认为通过半胱氨酸修饰来改变免疫相关蛋白质的功能；然而，我们对人类免疫蛋白质组中对电泳性敏感的半胱氨酸的了解仍然有限。在这里，我们提出了原代人类T细胞半胱氨酸的全球图谱，这些半胱氨酸对亲电小分子的共价修饰很敏感。在功能和结构不同的蛋白质上发现了3000多个共价连接的半胱氨酸，包括许多在免疫学中起基础作用的蛋白质。我们进一步表明，亲电化合物可以通过不同的机制损害T细胞的激活，这些机制涉及蛋白质的直接功能扰动和/或降解。我们的发现揭示了人类T细胞中丰富的可连接半胱氨酸的含量，并指出亲电小分子是化学探针的肥沃来源，最终是调节免疫过程及其相关疾病的治疗方法。集成的化学蛋白质组学和表型筛选提供了原代人类T细胞半胱氨酸反应性和配基能力的全球画像，并使发现抑制T细胞激活和促进免疫调节蛋白降解的亲电小分子成为可能。
Electrophilic compounds originating from nature or chemical synthesis have profound effects on immune cells. These compounds are thought to act by cysteine modification to alter the functions of immune-relevant proteins; however, our understanding of electrophile-sensitive cysteines in the human immune proteome remains limited. Here, we present a global map of cysteines in primary human T cells that are susceptible to covalent modification by electrophilic small molecules. More than 3000 covalently liganded cysteines were found on functionally and structurally diverse proteins, including many that play fundamental roles in immunology. We further show that electrophilic compounds can impair T-cell activation by distinct mechanisms involving the direct functional perturbation and/or degradation of proteins. Our findings reveal a rich content of ligandable cysteines in human T cells and point to electrophilic small molecules as a fertile source for chemical probes and ultimately therapeutics that modulate immunological processes and their associated disorders. Integrated chemical proteomics and phenotypic screening furnishes a global portrait of cysteine reactivity and ligandability in primary human T cells and enables the discovery of electrophilic small molecules that suppress T-cell activation and promote the degradation of immunomodulatory proteins.
登录
查看更多内容
影响因子：
7.3
作者：
Cai Q;Sun H;Peng Y;Lu J;Nikolovska-Coleska Z;McEachern D;Liu L;Qiu S;Yang CY;Miller R;Yi H;Zhang T;Sun D;Kang S;Guo M;Leopold L;Yang D;Wang S
通讯作者：
Wang S
影响因子：
14.9
作者：
The Gene Ontology Consortium
通讯作者：
The Gene Ontology Consortium
Biopython：用于计算分子生物学和生物信息学的免费 Python 工具。
DOI：
10.1093/bioinformatics/btp163
发表时间：
2009-06-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Cock PJ;Antao T;Chang JT;Chapman BA;Cox CJ;Dalke A;Friedberg I;Hamelryck T;Kauff F;Wilczynski B;de Hoon MJ
通讯作者：
de Hoon MJ
影响因子：
4
作者：
Buckley DL;Raina K;Darricarrere N;Hines J;Gustafson JL;Smith IE;Miah AH;Harling JD;Crews CM
通讯作者：
Crews CM
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y