The contribution of native protein complexes to targeted protein degradation

TY - JOUR

T1 - The contribution of native protein complexes to targeted protein degradation

AU - Glennie, Lorraine

AU - Curnutt, Nicole

AU - Sathe, Gajanan

AU - Le Chatelier, Brune

AU - Goff, Freya

AU - Zhao, Jin-Feng

AU - Cartwright, Tyrell

AU - Dunbar, Karen

AU - Wood, Nicola

AU - Macartney, Thomas

AU - Sapkota, Gopal

AU - Woo, Christina

N1 - Publisher Copyright: © 2026 The Authors. Published by American Chemical Society.

PY - 2026/5/15

Y1 - 2026/5/15

N2 - Targeted protein degradation (TPD) destroys proteins of interest (POIs) by hijacking the cellular proteolytic machinery. Most proteins in cells exist and function as part of multiprotein or macromolecular complexes, thereby allowing a single protein to control multiple biological processes. Therefore, when a small molecule degrader induces the proximity between an E3 ligase and the POI, the macromolecular context of the POI potentially influences the degradation outcomes of the POI and of the complex components. Here, we explore the degradation of the eight CK1α-SACK1 (formerly known as FAM83A-H) complexes initiated by molecular glue degraders primarily designed to target Ser/Thr kinase CK1α. We demonstrate that lenalidomide-derived degraders DEG-77 and SJ3149, which selectively target the CK1α isoform, codegrade multiple SACK1 proteins. We show that the degradation of SACK1 proteins by DEG-77 and SJ3149 requires CK1α, the CUL4A CRBN E3 ligase complex, and the proteasome. In cells derived from palmoplantar keratoderma patients harboring the CK1α-binding-deficient SACK1G R265P mutation, DEG-77 targets CK1α and mitotic SACK1D but not SACK1G R265P, highlighting the requirement for CK1α-SACK1 interaction to achieve codegradation. Our study underscores the importance of POI context in TPD and reinforces the potential for selectively targeting specific protein complexes for degradation.

AB - Targeted protein degradation (TPD) destroys proteins of interest (POIs) by hijacking the cellular proteolytic machinery. Most proteins in cells exist and function as part of multiprotein or macromolecular complexes, thereby allowing a single protein to control multiple biological processes. Therefore, when a small molecule degrader induces the proximity between an E3 ligase and the POI, the macromolecular context of the POI potentially influences the degradation outcomes of the POI and of the complex components. Here, we explore the degradation of the eight CK1α-SACK1 (formerly known as FAM83A-H) complexes initiated by molecular glue degraders primarily designed to target Ser/Thr kinase CK1α. We demonstrate that lenalidomide-derived degraders DEG-77 and SJ3149, which selectively target the CK1α isoform, codegrade multiple SACK1 proteins. We show that the degradation of SACK1 proteins by DEG-77 and SJ3149 requires CK1α, the CUL4A CRBN E3 ligase complex, and the proteasome. In cells derived from palmoplantar keratoderma patients harboring the CK1α-binding-deficient SACK1G R265P mutation, DEG-77 targets CK1α and mitotic SACK1D but not SACK1G R265P, highlighting the requirement for CK1α-SACK1 interaction to achieve codegradation. Our study underscores the importance of POI context in TPD and reinforces the potential for selectively targeting specific protein complexes for degradation.

U2 - 10.1021/acschembio.6c00098

DO - 10.1021/acschembio.6c00098

M3 - Article

SN - 1554-8929

VL - 21

SP - 1095

EP - 1111

JO - ACS Chemical Biology

JF - ACS Chemical Biology

IS - 5

ER -