Structural basis for LZTR1 recognition of RAS GTPases for degradation

• 成果类型: Article
• 署名作者: Dharmaiah, Srisathiyanarayanan; Bonsor, Daniel A.; Mo, Stephanie P.; Fernandez-Cabrera, Alvaro; Chan, Albert H.; Messing, Simon; Drew, Matthew; Vega, Martha; Nissley, Dwight V.; Esposito, Dominic; Castel, Pau; Simanshu, Dhirendra K.
• 署名单位: National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); Frederick National Laboratory for Cancer Research
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-11109
• DOI: 10.1126/science.adv7088
• 发表日期: 2025-09-11
• 页码: 1112-1117
• 关键词: dynamic properties; protein; gtp; refinement; features; binding; rit

摘要

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.