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Critical protein-protein interactions within the CARMA1-BCL10-MALT1 complex: Take-home points for the cell biologist.
Cellular Immunology ( IF 4.3 ) Pub Date : 2020-07-07 , DOI: 10.1016/j.cellimm.2020.104158
Jing Cheng 1 , Lisa M Maurer 1 , Heejae Kang 2 , Peter C Lucas 2 , Linda M McAllister-Lucas 1
Affiliation  

The CBM complex, which is composed of the proteins CARMA1, BCL10, and MALT1, serves multiple pivotal roles as a mediator of T-cell receptor and B-cell receptor-dependent NF-κB induction and lymphocyte activation. CARMA1, BCL10, and MALT1 are each proto-oncoproteins and dysregulation of CBM signaling, as a result of somatic gain-of-function mutation or chromosomal translocation, is a hallmark of multiple lymphoid malignancies including Activated B-cell Diffuse Large B-cell Lymphoma. Moreover, loss-of-function as well as gain-of-function germline mutations in CBM complex proteins have been associated with a range of immune dysregulation syndromes. A wealth of detailed structural information has become available over the past decade through meticulous interrogation of the interactions between CBM components. Here, we review key findings regarding the biochemical nature of these protein-protein interactions which have ultimately led the field to a sophisticated understanding of how these proteins assemble into high-order filamentous CBM complexes. To date, approaches to therapeutic inhibition of the CBM complex for the treatment of lymphoid malignancy and/or auto-immunity have focused on blocking MALT1 protease function. We also review key studies relating to the structural impact of MALT1 protease inhibitors on key protein-protein interactions.



中文翻译:

CARMA1-BCL10-MALT1 复合物中的关键蛋白质-蛋白质相互作用:细胞生物学家的重点。

CBM 复合物由蛋白质 CARMA1、BCL10 和 MALT1 组成,作为T-细胞受体和 B 细胞受体依赖性 NF-κB 诱导和淋巴细胞活化。CARMA1、BCL10 和 MALT1 都是原癌蛋白,由于体细胞功能获得性突变或染色体易位导致 CBM 信号失调,是多种淋巴恶性肿瘤的标志,包括激活的 B 细胞弥漫性大 B 细胞淋巴瘤. 此外,CBM 复合蛋白中功能丧失和功能获得的种系突变与一系列免疫失调综合征有关。在过去十年中,通过对 CBM 组件之间相互作用的细致询问,可以获得大量详细的结构信息。这里,我们回顾了关于这些蛋白质-蛋白质相互作用的生化性质的关键发现,这些发现最终使该领域对这些蛋白质如何组装成高阶丝状 CBM 复合物有了深入的了解。迄今为止,用于治疗淋巴恶性肿瘤和/或自身免疫的 CBM 复合物的治疗性抑制方法主要集中在阻断 MALT1 蛋白酶功能上。我们还回顾了与 MALT1 蛋白酶抑制剂对关键蛋白质-蛋白质相互作用的结构影响相关的关键研究。

更新日期:2020-07-25
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