Boc3Arg-Linked Ligands Induce Degradation by Localizing Target Proteins to the 20S Proteasome

Yuntao Shi; Marcus J.C Long; Masha M Rosenberg; Shican Li; Aimee Kobjack; Philip Lessans; Rory T Coffey; Lizbeth Hedstrom

doi:10.1021/acschembio.6b00656

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Boc3Arg-Linked Ligands Induce Degradation by Localizing Target Proteins to the 20S Proteasome

Journal article

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Boc3Arg-Linked Ligands Induce Degradation by Localizing Target Proteins to the 20S Proteasome

Yuntao Shi, Marcus J.C Long, Masha M Rosenberg, Shican Li, Aimee Kobjack, Philip Lessans, Rory T Coffey and Lizbeth Hedstrom

ACS chemical biology, Vol.11(12), pp.3328-3337

10/05/2016

DOI: https://doi.org/10.1021/acschembio.6b00656

PMCID: PMC5524191

PMID: 27704767

Abstract

Degradation

Peptides and proteins

Post-translational modification

Ligands

Inhibitors

Targeted protein degradation is a promising strategy for drug design and functional assessment. Several small molecule approaches have been developed that localize target proteins to ubiquitin ligases, inducing ubiquitination and subsequent degradation by the 26S proteasome. We discovered that the degradation of a target protein can also be induced by a recognition ligand linked to tert-butyl carbamate (Boc3)-protected arginine (B3A). Here, we show that this process requires the proteasome but does not involve ubiquitination of the target protein. B3A does not perturb the structure of the target protein; instead, a B3A-ligand stabilizes its target protein. B3A ligands stimulate activity of purified 20S proteasome, demonstrating that the tag binds directly to the 20S proteasome. Moreover, purified 20S proteasome is sufficient to degrade target proteins in the presence of their respective B3A-linked recognition ligands. These observations suggest a simple model for B3A-mediated degradation wherein the B3A tag localizes target proteins directly to the 20S proteasome. Thus, B3A ligands are the first example of a ubiquitin-free strategy for targeted protein degradation.

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Title: Boc3Arg-Linked Ligands Induce Degradation by Localizing Target Proteins to the 20S Proteasome
Creators: Yuntao Shi - Graduate Program in Chemistry, ‡Graduate Program in Biochemistry and Biophysics, §Department of Biology, ∥Graduate Program in Molecular and Cell Biology, Brandeis University, Waltham, Massachusetts, United States, Department of Biochemistry, #Department of Chemistry, Brandeis University, Waltham, Massachusetts, United States
Marcus J.C Long - Graduate Program in Chemistry, ‡Graduate Program in Biochemistry and Biophysics, §Department of Biology, ∥Graduate Program in Molecular and Cell Biology, Brandeis University, Waltham, Massachusetts, United States, Department of Biochemistry, #Department of Chemistry, Brandeis University, Waltham, Massachusetts, United States
Masha M Rosenberg - Graduate Program in Chemistry, ‡Graduate Program in Biochemistry and Biophysics, §Department of Biology, ∥Graduate Program in Molecular and Cell Biology, Brandeis University, Waltham, Massachusetts, United States, Department of Biochemistry, #Department of Chemistry, Brandeis University, Waltham, Massachusetts, United States
Shican Li - Graduate Program in Chemistry, ‡Graduate Program in Biochemistry and Biophysics, §Department of Biology, ∥Graduate Program in Molecular and Cell Biology, Brandeis University, Waltham, Massachusetts, United States, Department of Biochemistry, #Department of Chemistry, Brandeis University, Waltham, Massachusetts, United States
Aimee Kobjack - Graduate Program in Chemistry, ‡Graduate Program in Biochemistry and Biophysics, §Department of Biology, ∥Graduate Program in Molecular and Cell Biology, Brandeis University, Waltham, Massachusetts, United States, Department of Biochemistry, #Department of Chemistry, Brandeis University, Waltham, Massachusetts, United States
Philip Lessans - Graduate Program in Chemistry, ‡Graduate Program in Biochemistry and Biophysics, §Department of Biology, ∥Graduate Program in Molecular and Cell Biology, Brandeis University, Waltham, Massachusetts, United States, Department of Biochemistry, #Department of Chemistry, Brandeis University, Waltham, Massachusetts, United States
Rory T Coffey - Graduate Program in Chemistry, ‡Graduate Program in Biochemistry and Biophysics, §Department of Biology, ∥Graduate Program in Molecular and Cell Biology, Brandeis University, Waltham, Massachusetts, United States, Department of Biochemistry, #Department of Chemistry, Brandeis University, Waltham, Massachusetts, United States
Lizbeth Hedstrom - Graduate Program in Chemistry, ‡Graduate Program in Biochemistry and Biophysics, §Department of Biology, ∥Graduate Program in Molecular and Cell Biology, Brandeis University, Waltham, Massachusetts, United States, Department of Biochemistry, #Department of Chemistry, Brandeis University, Waltham, Massachusetts, United States
Publication Details: ACS chemical biology, Vol.11(12), pp.3328-3337
Identifiers: 9923972811801921
Academic Unit: Department of Chemistry; Department of Biology
Language: English
Resource Type: Journal article

Boc3Arg-Linked Ligands Induce Degradation by Localizing Target Proteins to the 20S Proteasome

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