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致病性变异破坏 CAD 寡聚化。

Disruption of CAD Oligomerization by Pathogenic Variants.

机构信息

Structure of Macromolecular Targets Unit, Instituto de Biomedicina de Valencia (IBV), CSIC, Eduardo Primo Yúfera, 3, 46012 Valencia, Spain.

Molecular Oncology Laboratory, Hospital Clínico San Carlos, IdISSC (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Prof Marín Lagos, S/N, 28040 Moncloa-Aravaca, Madrid, Spain.

出版信息

J Mol Biol. 2024 Dec 1;436(23):168832. doi: 10.1016/j.jmb.2024.168832. Epub 2024 Oct 22.

Abstract

CAD, the multi-enzymatic protein essential for initiating the de novo biosynthesis of pyrimidine nucleotides, forms large hexamers whose structure and function are not fully understood. Defects in CAD cause a severe neurometabolic disorder that is challenging to diagnose. We developed a cellular functional assay to identify defective CAD variants, and in this study, we characterized five pathogenic missense mutations in CAD's dihydroorotase (DHO) and aspartate transcarbamoylase (ATC) domains. All mutations impaired enzymatic activities, with two notably disrupting the formation of DHO dimers and ATC trimers. Combining crystal structures and AlphaFold predictions, we modeled the hexameric CAD complex, highlighting the central role of the DHO and ATC domains in its assembly. Our findings provide insight into CAD's stability, function, and organization, revealing that correct oligomerization of CAD into a supramolecular complex is required for its function in nucleotide synthesis and that mutations affecting this assembly are potentially pathogenic.

摘要

CAD 是从头合成嘧啶核苷酸所必需的多酶蛋白,形成其结构和功能尚未完全了解的大型六聚体。CAD 的缺陷会导致严重的神经代谢紊乱,难以诊断。我们开发了一种细胞功能测定法来识别有缺陷的 CAD 变体,在本研究中,我们对 CAD 的二氢乳清酸酶 (DHO) 和天冬氨酸转氨甲酰酶 (ATC) 结构域中的五个致病性错义突变进行了表征。所有突变都损害了酶活性,其中两个突变特别破坏了 DHO 二聚体和 ATC 三聚体的形成。结合晶体结构和 AlphaFold 预测,我们对六聚体 CAD 复合物进行了建模,突出了 DHO 和 ATC 结构域在其组装中的核心作用。我们的研究结果提供了对 CAD 稳定性、功能和组织的深入了解,表明 CAD 正确地形成超分子复合物进行核苷酸合成对于其功能是必需的,并且影响这种组装的突变可能是潜在的致病因素。

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