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The Contribution of Native Protein Complexes to Targeted Protein Degradation.

Lorraine Glennie1, Nicole M Curnutt2,3, Gajanan Sathe1

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Summary

Targeted protein degradation (TPD) using molecular glues can degrade multiple proteins within a complex. This study shows CK1α-SACK1 complexes are codegraded, highlighting the importance of protein context in TPD strategies.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Drug Discovery

Background:

  • Targeted protein degradation (TPD) leverages cellular machinery to eliminate specific proteins.
  • Proteins often function in complexes, influencing degradation outcomes.
  • Understanding protein complex dynamics is crucial for effective TPD.

Purpose of the Study:

  • To investigate the degradation of CK1α-SACK1 complexes using molecular glue degraders.
  • To explore how the macromolecular context affects TPD of protein complexes.
  • To assess the role of CK1α-SACK1 interaction in codegradation.

Main Methods:

  • Utilized lenalidomide-derived degraders (DEG-77, SJ3149) targeting CK1α.
  • Examined degradation of SACK1 proteins within CK1α-SACK1 complexes.
  • Assessed the requirement of CK1α, CUL4ACRBN E3 ligase, and proteasome for degradation.
  • Studied degradation in patient-derived cells with a CK1α-binding-deficient SACK1 mutation.

Main Results:

  • DEG-77 and SJ3149 codegraded multiple SACK1 proteins within the CK1α-SACK1 complex.
  • Degradation required CK1α, CUL4ACRBN E3 ligase, and the proteasome.
  • A SACK1 mutation preventing CK1α binding inhibited codegradation, confirming the interaction's necessity.
  • Degraders selectively targeted CK1α and certain SACK1 isoforms.

Conclusions:

  • Protein context significantly influences targeted protein degradation outcomes.
  • Molecular glues can effectively induce codegradation of proteins within a complex.
  • CK1α-SACK1 interaction is essential for degrader-induced codegradation.
  • This highlights the potential for TPD to target specific protein complexes.