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Rab proteins constitute the largest family of monomeric GTPases, of which 70 members are present in humans. Rab proteins and their effectors regulate consecutive stages of vesicle transport such as vesicle transport, docking, and fusion to the correct recipient membrane.
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The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
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Structural basis for LZTR1 recognition of RAS GTPases for degradation.

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Science (New York, N.Y.)
|September 11, 2025
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Summary
This summary is machine-generated.

Leucine Zipper-like Transcription Regulator 1 (LZTR1) targets RAS GTPases for degradation. Understanding LZTR1’s RAS binding mechanisms reveals insights into RAS signaling and potential therapeutic strategies for KRAS-driven cancers.

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Area of Science:

  • Molecular Biology
  • Structural Biology
  • Cellular Signaling

Background:

  • RAS GTPases are crucial signaling proteins regulated by ubiquitination and proteolysis.
  • Leucine Zipper-like Transcription Regulator 1 (LZTR1) acts as a substrate adapter for Cullin-3 RING E3 ubiquitin ligase, targeting specific RAS proteins for degradation.
  • Dysregulation of RAS signaling is implicated in various cancers.

Purpose of the Study:

  • To elucidate the structural basis of LZTR1's interaction with RAS GTPases.
  • To understand how LZTR1 achieves RAS isoform selectivity and nucleotide specificity.
  • To investigate the functional consequences of disease-associated LZTR1 mutations.

Main Methods:

  • X-ray crystallography to determine the structures of LZTR1 Kelch domains bound to RIT1, MRAS, and KRAS.
  • Biochemical assays to analyze substrate interactions and mutation effects.
  • Cellular and mouse models to assess the in vivo impact of LZTR1 mutations.

Main Results:

  • Detailed structures reveal the interfaces governing RAS isoform and nucleotide specificity.
  • Disease-associated mutations in LZTR1's Kelch domain lead to impaired substrate binding, loop destabilization, or blade-blade repulsion.
  • Mutations disrupting substrate binding phenocopy LZTR1 loss in cellular and mouse models, confirming LZTR1's substrate specificity.

Conclusions:

  • LZTR1 recognizes specific RAS GTPases through defined structural interfaces.
  • Understanding these recognition mechanisms provides a foundation for developing targeted therapies.
  • The findings suggest a potential molecular glue strategy to degrade oncogenic KRAS.