Antibody RING-Mediated Destruction of Endogenous Proteins

Ibrahim, Adel; Shen, Linnan; Tatham, Michael H.; Dickerson, David; Prescott, Alan R.; Abidi, Naima; Xirodimas, Dimitris P.; Hay, Ronald T.

doi:10.1016/j.molcel.2020.04.032

Cited by 46 publications

(43 citation statements)

References 43 publications

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“…Together, this work greatly expands the Trim-Away technology toolbox beyond the use of standard antibodies and allows more flexibility when designing protein depletion experiments utilising TRIM21. In addition to Trim-Away there are a growing number of methods available for acutely controlling endogenous protein levels (Baudisch et al, 2018;Caussinus et al, 2012;Clift et al, 2017;Clift et al, 2018;Deng et al, 2020;Fulcher et al, 2016;Gross et al, 2016;Ibrahim et al, 2020;Ju Shin et al, 2015;Lim et al, 2020;Ludwicki et al, 2019;Marschall et al, 2014;Portnoff et al, 2014;Traub, 2019;Yamaguchi et al, 2019). However, our work here on TRIM21 provides the first mechanistic understanding of how an E3 ligase can be re-directed to degrade diverse non-canonical substrates.…”

Section: Discussionmentioning

confidence: 99%

Substrate-induced clustering activates Trim-Away of pathogens and proteins

Zeng

Santos

Mukadam

et al. 2020

Preprint

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SUMMARYTrim-Away is a powerful new technology that exploits off-the-shelf antibodies and the E3 RING ligase and cytosolic antibody receptor TRIM21 to carry out rapid protein depletion. How TRIM21 is catalytically-activated upon substrate engagement during either its normal immune function or when re-purposed for targeted protein degradation is unknown. Here we show that a mechanism of substrate-induced clustering triggers intermolecular dimerization of the RING domain to switch on the ubiquitination activity of TRIM21 and induce an antiviral response or drive Trim-Away. We harness this mechanism to expand the Trim-Away toolbox with highly-active TRIM21-nanobody chimeras that can also be controlled optogenetically. This work provides a mechanism for cellular activation of TRIM RING ligases and has important implications for targeted protein degradation technologies.

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Section: Discussionmentioning

confidence: 99%

Substrate-induced clustering activates Trim-Away of pathogens and proteins

Zeng

Santos

Mukadam

et al. 2020

Preprint

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“…Antibodies have also been utilized to degrade endogenous proteins with technologies such as “Trim-Away” ( 130 ). More recently, nanobodies have also been coupled to RING proteins to achieve highly selective degradation of target proteins ( 131 ). Clinically, these additional controlled mechanisms on PROTACs may allow for localized degradation.…”

Section: Hijacking Of the Ups: Protacsmentioning

confidence: 99%

Major advances in targeted protein degradation: PROTACs, LYTACs, and MADTACs

Alabi

Crews

2021

Journal of Biological Chemistry

146

122

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Of late, targeted protein degradation (TPD) has surfaced as a novel and innovative chemical tool and therapeutic modality. By co-opting protein degradation pathways, TPD facilitates complete removal of the protein molecules from within or outside the cell. While the pioneering Proteolysis-Targeting Chimera (PROTAC) technology and molecular glues hijack the ubiquitin-proteasome system, newer modalities co-opt autophagy or the endo-lysosomal pathway. Using this mechanism, TPD is posited to largely expand the druggable space far beyond small-molecule inhibitors. In this review, we discuss the major advances in TPD, highlight our current understanding, and explore outstanding questions in the field.

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“…Research use [159] Protac for tagged proteins Allosteric modulator Estrogen receptor ND (indirectly, CHIP) Oncology: breast cancer [134,136] * Therapeutic potential as reported in the corresponding reference.…”

Section: Rnf4mentioning

confidence: 99%

“…In a similar way, Ibrahim et al [ 159 ] devised a method based on the specific interaction of an antibody fused to the RING domain of the ubiquitin E3 ligase RNF4 (ARMeD, antibody RING-mediated destruction). The objective of this work was to engineer a single-component system that could be easily produced and used as a reagent to induce POI degradation.…”

Section: Modulating the Reactivity And Versatility Of Proteolytic mentioning

confidence: 99%

The Potential of Proteolytic Chimeras as Pharmacological Tools and Therapeutic Agents

2020

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The induction of protein degradation in a highly selective and efficient way by means of druggable molecules is known as targeted protein degradation (TPD). TPD emerged in the literature as a revolutionary idea: a heterobifunctional chimera with the capacity of creating an interaction between a protein of interest (POI) and a E3 ubiquitin ligase will induce a process of events in the POI, including ubiquitination, targeting to the proteasome, proteolysis and functional silencing, acting as a sort of degradative knockdown. With this programmed protein degradation, toxic and disease-causing proteins could be depleted from cells with potentially effective low drug doses. The proof-of-principle validation of this hypothesis in many studies has made the TPD strategy become a new attractive paradigm for the development of therapies for the treatment of multiple unmet diseases. Indeed, since the initial protacs (Proteolysis targeting chimeras) were posited in the 2000s, the TPD field has expanded extraordinarily, developing innovative chemistry and exploiting multiple degradation approaches. In this article, we review the breakthroughs and recent novel concepts in this highly active discipline.

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Antibody RING-Mediated Destruction of Endogenous Proteins

Abstract: Highlights d Antibody RING-mediated destruction (ARMeD) targets endogenous proteins for degradation d ARMeD is mediated by a nanobody fused to the RING domain of ubiquitin E3 ligase RNF4 d Nanobody-RING fusions introduced into cells degrade target proteins within minutes

Cited by 46 publications

References 43 publications

Substrate-induced clustering activates Trim-Away of pathogens and proteins

Substrate-induced clustering activates Trim-Away of pathogens and proteins

Major advances in targeted protein degradation: PROTACs, LYTACs, and MADTACs

The Potential of Proteolytic Chimeras as Pharmacological Tools and Therapeutic Agents

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