Structural basis for LZTR1 recognition of RAS GTPases for degradation

IF 45.8 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Pub Date : 2025-09-11 DOI:10.1126/science.adv7088

Srisathiyanarayanan Dharmaiah, Daniel A. Bonsor, Stephanie P. Mo, Alvaro Fernandez-Cabrera, Albert H. Chan, Simon Messing, Matthew Drew, Martha Vega, Dwight V. Nissley, Dominic Esposito, Pau Castel, Dhirendra K. Simanshu

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引用次数: 0

Abstract

The RAS family of small guanosine triphosphatases (GTPases) are tightly regulated signaling molecules that are further modulated by ubiquitination and proteolysis. Leucine Zipper-like Transcription Regulator 1 (LZTR1), a substrate adapter of the Cullin-3 RING E3 ubiquitin ligase, binds specific RAS GTPases and promotes their ubiquitination and proteasomal degradation. We present structures of LZTR1 Kelch domains bound to RIT1, MRAS, and KRAS, revealing interfaces that govern RAS isoform selectivity and nucleotide specificity. Biochemical and structural analyses of disease-associated Kelch domain mutations revealed three types of alterations: impaired substrate interaction, loop destabilization, and blade-blade repulsion. In cellular and mouse models, mutations disrupting substrate binding phenocopied LZTR1 loss, underscoring its substrate specificity. These findings define RAS recognition mechanisms by LZTR1 and suggest a molecular glue strategy to degrade oncogenic KRAS.

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LZTR1识别RAS GTPases进行降解的结构基础。

RAS家族的小鸟苷三磷酸酶（gtpase）是受到严格调控的信号分子，可通过泛素化和蛋白水解进一步调节。亮氨酸拉链样转录调节因子1 （LZTR1）是Cullin-3环E3泛素连接酶的底物适配器，可结合特异性RAS gtpase并促进其泛素化和蛋白酶体降解。我们展示了与RIT1、MRAS和KRAS结合的LZTR1 Kelch结构域的结构，揭示了控制RAS异构体选择性和核苷酸特异性的界面。疾病相关Kelch结构域突变的生化和结构分析揭示了三种类型的改变：底物相互作用受损、环不稳定和叶片-叶片排斥。在细胞和小鼠模型中，破坏底物结合的突变导致LZTR1缺失，强调了其底物特异性。这些发现明确了LZTR1对RAS的识别机制，并提出了一种降解致癌KRAS的分子胶策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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