小柯机器人

瑞典斯德哥尔摩大学Marta Carroni、美国因斯布鲁克医科大学Bernhard Rupp等研究人员合作发现，神经纤维瘤蛋白亚型2的结构显示出不同的功能状态。该研究于2021年10月27日发表于国际一流学术期刊《自然》杂志上。

研究人员以3.3埃的整体分辨率确定了人类神经纤维瘤蛋白（Nf1）二聚体结构。冷冻电镜结构揭示了Nf1外显子23a剪接亚型2在封闭、自抑制、Zn稳定状态和开放状态下的结构域组织和结构细节。在闭合构象中，HEAT/ARM核心结构域屏蔽了GTP酶激活蛋白相关结构域（GRD），从而使Ras的结合受到了立体抑制。

在一个明显不同的开放构象中，GRD发生了大规模的移动，这是接触Ras所必需的，而Sec14-PH则重新定向以允许与细胞膜的相互作用。Nf1的Zn孵育导致Ras-GAP活性降低，两个模体都处于自我抑制的封闭构象，由N-HEAT/ARM结构域和GRD-Sec14-PH连接体之间的Zn结合点稳定。Nf1的封闭、自我抑制状态和开放状态之间的转变为破译广泛的神经纤维瘤病综合征和Nf1在致癌过程中功能障碍背后复杂分子机制的靶标研究提供了指导。

据了解，常染色体显性单基因疾病1型神经纤维瘤病（NF1）大约影响每三千分之一人的人口，由NF1肿瘤抑制基因的突变引起，导致Nf1蛋白的功能紊乱。作为一种GTP酶激活蛋白，Nf1的一个关键功能是抑制Ras致癌基因信号级联。

附：英文原文

Title: The structure of neurofibromin isoform 2 reveals different functional states

Author: Naschberger, Andreas, Baradaran, Rozbeh, Rupp, Bernhard, Carroni, Marta

Issue&Volume: 2021-10-27

Abstract: The autosomal dominant monogenetic disease neurofibromatosis type 1 (NF1) affects approximately one in 3,000 individuals and is caused by mutations in the NF1 tumour suppressor gene, leading to dysfunction in the protein neurofibromin (Nf1)1,2. As a GTPase-activating protein, a key function of Nf1 is repression of the Ras oncogene signalling cascade. We determined the human Nf1 dimer structure at an overall resolution of 3.3. The cryo-electron microscopy structure reveals domain organization and structural details of the Nf1 exon 23a splicing3 isoform 2 in a closed, self-inhibited, Zn-stabilized state and an open state. In the closed conformation, HEAT/ARM core domains shield the GTPase-activating protein-related domain (GRD) so that Ras binding is sterically inhibited. In a distinctly different, open conformation of one protomer, a large-scale movement of the GRD occurs, which is necessary to access Ras, whereas Sec14-PH reorients to allow interaction with the cellular membrane4. Zn incubation of Nf1 leads to reduced Ras-GAP activity with both protomers in the self-inhibited, closed conformation stabilized by a Zn binding site between the N-HEAT/ARM domain and the GRD–Sec14-PH linker. The transition between closed, self-inhibited states of Nf1 and open states provides guidance for targeted studies deciphering the complex molecular mechanism behind the widespread neurofibromatosis syndrome and Nf1 dysfunction in carcinogenesis.

DOI: 10.1038/s41586-021-04024-x

Source: https://www.nature.com/articles/s41586-021-04024-x

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