Structural basis for LZTR1 recognition of RAS GTPases for degradation

  • Science. 2025 Sep 11;389(6765):1112-1117. doi: 10.1126/science.adv7088.
Srisathiyanarayanan Dharmaiah  #  1 ,  Daniel A Bonsor  #  1 ,  Stephanie P Mo  #  2 ,  Alvaro Fernandez-Cabrera  2 ,  Albert H Chan  1 ,  Simon Messing  1 ,  Matthew Drew  1 ,  Martha Vega  2 ,  Dwight V Nissley  1 ,  Dominic Esposito  1 ,  Pau Castel  2 ,  Dhirendra K Simanshu  1
Affiliations
  • 1. National Cancer Institute RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
  • 2. Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA.
  • # Contributed equally.
PMID: 40934300 DOI: 10.1126/science.adv7088
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.