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Structural basis of selective ubiquitination of TRF1 by SCFFbx4.

TRF1 is a critical regulator of telomere length. As such, TRF1 levels are regulated by ubiquitin-dependent proteolysis via an SCF E3 ligase where Fbx4 contributes to substrate specification. Here, we report the crystal structure of the Fbx4-TRF1 complex at 2.4 A resolution. Fbx4 contains an unusual substrate-binding domain that adopts a small GTPase fold. Strikingly, this atypical GTPase domain of Fbx4 binds to a globular domain of TRF1 through an intermolecular beta sheet, instead of recognizing short peptides/degrons as often seen in other F-box protein-substrate complexes. Importantly, mutations in this interface abrogate Fbx4-dependent TRF1 binding and ubiquitination. Furthermore, the data demonstrate that recognition of TRF1 by SCF(Fbx4) is regulated by another telomere protein, TIN2. Our results reveal an atypical small GTPase domain within Fbx4 as a substrate-binding motif for SCF(Fbx4) and uncover a mechanism for selective ubiquitination and degradation of TRF1 in telomere homeostasis control.

Pubmed ID: 20159592


  • Zeng Z
  • Wang W
  • Yang Y
  • Chen Y
  • Yang X
  • Diehl JA
  • Liu X
  • Lei M


Developmental cell

Publication Data

February 16, 2010

Associated Grants

  • Agency: NCI NIH HHS, Id: CA 107098
  • Agency: NIGMS NIH HHS, Id: GM 083015-01
  • Agency: NCI NIH HHS, Id: Y1-CO-1020
  • Agency: NIGMS NIH HHS, Id: Y1-GM-1104
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Amino Acid Sequence
  • Base Sequence
  • Binding Sites
  • Cell Line
  • Crystallography, X-Ray
  • Homeostasis
  • Humans
  • In Vitro Techniques
  • Models, Molecular
  • Monomeric GTP-Binding Proteins
  • Multiprotein Complexes
  • Mutation
  • Protein Processing, Post-Translational
  • Protein Stability
  • Protein Structure, Tertiary
  • RNA, Small Interfering
  • Recombinant Fusion Proteins
  • SKP Cullin F-Box Protein Ligases
  • Sequence Homology, Amino Acid
  • Substrate Specificity
  • Telomere
  • Telomere-Binding Proteins
  • Telomeric Repeat Binding Protein 1
  • Two-Hybrid System Techniques
  • Ubiquitination