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Repurposing an endogenous degradation domain for antibody-mediated disposal of cell-surface proteins.

ABSTRACT: The exquisite specificity of antibodies can be harnessed to effect targeted degradation of membrane proteins. Here, we demonstrate targeted protein removal utilising a protein degradation domain derived from the endogenous human protein Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9). Recombinant antibodies genetically fused to this domain drive the degradation of membrane proteins that undergo constitutive internalisation and recycling, including the transferrin receptor and the human cytomegalovirus latency-associated protein US28. We term this approach PACTAC (PCSK9-Antibody Clearance-Targeting Chimeras).

SUBMITTER: Schmitt J

PROVIDER: S-EPMC10933360 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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Repurposing an endogenous degradation domain for antibody-mediated disposal of cell-surface proteins.

Schmitt Janika J Poole Emma E Groves Ian I Owen David J DJ Graham Stephen C SC Sinclair John J Kelly Bernard T BT

EMBO reports 20240129 3

The exquisite specificity of antibodies can be harnessed to effect targeted degradation of membrane proteins. Here, we demonstrate targeted protein removal utilising a protein degradation domain derived from the endogenous human protein Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9). Recombinant antibodies genetically fused to this domain drive the degradation of membrane proteins that undergo constitutive internalisation and recycling, including the transferrin receptor and the human cyt ...[more]

PMID: 38287192

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