Blocking an N-terminal acetylation–dependent protein interaction inhibits an E3 ligase

Scott, Daniel C.; Hammill, Jared T.; Min, Jaeki; Rhee, David Y.; Connelly, Michele; Sviderskiy, Vladislav O.; Bhasin, Deepak K.; Chen, Yizhe; Ong, Su-Sien; Chai, Sergio C.; Goktug, Asli N.; Huang, Guochang; Monda, Julie K.; Low, Jonathan; Kim, Ho Shin; Paulo, João A.; Cannon, Joe R.; Shelat, Anang A.; Chen, Taosheng; Kelsall, Ian R.; Alpi, Arno F.; Pagala, Vishwajeeth; Wang, Xusheng; Peng, Junmin; Singh, Bhuvanesh; Harper, J. Wade; Schulman, Brenda A.; Guy, R. Kiplin

doi:10.1038/nchembio.2386

Cited by 77 publications

(166 citation statements)

References 60 publications

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“…The NatC Nt-acetylated Met-1 of the E2 enzyme UBC12 (human UBE2M) binds in a hydrophobic pocket in E3 DCN1 (human DCUN1D1) (Scott et al, 2011), and this type of interaction is common for mammalian NEDD8 ligation enzymes (Monda et al, 2013). This direct involvement of the Nt acetyl group in protein binding was recently antagonized by inhibitors with selectivity for the Nt acetyl pockets of DCN1 and DCN2 (Scott et al, 2017). Nt acetylation may also indirectly affect binding, such as for Sir3's binding to the nucleosome, in which the Nt acetylation dependency is explained by stabilization of a binding loop (Arnaudo et al, 2013;Yang et al, 2013).…”

Section: The Eukaryotic Nat Machinerymentioning

confidence: 99%

Co-translational, Post-translational, and Non-catalytic Roles of N-Terminal Acetyltransferases

2019

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Section: The Eukaryotic Nat Machinerymentioning

confidence: 99%

Co-translational, Post-translational, and Non-catalytic Roles of N-Terminal Acetyltransferases

2019

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“…Previously, we reported a newly developed compound that specifically inhibits SCCRO and SCCRO2 activity by interfering with their interactions with UBC12 (25). This novel compound was used to screen for SCCRO-dependent, substrate-specific BTB-Kelch proteins that serve as adaptors in Cul3-anchored CRLs (25). Use of the inhibitor allowed the identification of binding interaction that acutely depends on the neddylation activity of SCCRO.…”

Section: Sccro Promotes Assembly Of Cul3 Klhl21 At the Midbodymentioning

confidence: 99%

Squamous cell carcinoma–related oncogene (SCCRO) neddylates Cul3 protein to selectively promote midbody localization and activity of Cul3KLHL21 protein complex during abscission

Huang¹,

Kaufman²,

et al. 2017

Journal of Biological Chemistry

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Squamous cell carcinoma-related oncogene (SCCRO)/DCUN1D1, a component of the neddylation E3 complex, regulates the activity of the cullin-RING-ligase type of ubiquitination E3s by promoting neddylation of cullin family members. Studies have shown that SCCRO regulates proliferation and Here we show that inactivation of SCCRO results in prolonged mitotic time because of delayed and/or failed abscission. The effects of SCCRO on abscission involve its role in neddylation and localization of Cul3 to the midbody. The Cul3 adaptor KLHL21 mediates the effects of SCCRO on abscission, as it fails to localize to the midbody in SCCRO-deficient cells during abscission, and its inactivation resulted in phenotypic changes identical to SCCRO inactivation. Ubiquitination-promoted turnover of Aurora B at the midbody was deficient in SCCRO- and KLHL21-deficient cells, suggesting that it is the target of Cul3 at the midbody. Correction of abscission delays in SCCRO-deficient cells with addition of an Aurora B inhibitor at the midbody stage suggests that Aurora B is the target of SCCRO-promoted Cul3 activity. The activity of other Cul3-anchored complexes, including Cul3, was intact in SCCRO-deficient cells, suggesting that SCCRO selectively, rather than collectively, neddylates cullins Combined, these findings support a model in which the SCCRO, substrate, and substrate adaptors cooperatively provide tight control of neddylation and cullin-RING-ligase activity.

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“…Interestingly, two of these 10 proteins are involved in pathways relevant to proteasome inhibition and HSPs, respectively (Figure 7E). Defective In Cullin Neddylation 1 Domain Containing 1 (DCUN1D1) is part of an E3 ubiquitin ligase complex for neddylation, and heat shock protein 70 kDa member 8 (HSPA8) is integral to the HSP70 pathway and cellular protein quality control systems (33,34). Notably, the DCUN1D1 mutation was unique to the PDX and cell line ( Figure 7E), suggesting the tumor from which this PDX was derived may have harbored unique genetics that could contribute to increased bortezomib sensitivity.…”

Section: Integration Of Whole Exome Sequencing and Ubiquitin Proteomimentioning

confidence: 99%

From the Clinic to the Bench and Back Again in One Dog Year: How a Cross-Species Pipeline to Identify New Treatments for Sarcoma Illuminates the Path Forward in Precision Medicine

et al. 2020

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Cancer drug discovery is an inefficient process, with more than 90% of newly-discovered therapies failing to gain regulatory approval. Patient-derived models of cancer offer a promising new approach to identify new treatments; however, for rare cancers, such as sarcomas, access to patient samples is limited, which precludes development of patient-derived models. To address the limited access to patient samples, we have turned to pet dogs with naturally-occurring sarcomas. Although sarcomas make up <1% of all human cancers, sarcomas represent 15% of cancers in dogs. Because dogs have similar immune systems, an accelerated pace of cancer progression, and a shared environment with humans, studying pet dogs with cancer is ideal for bridging gaps between mouse models and human cancers. Here, we present our cross-species personalized medicine pipeline to identify new therapies for sarcomas. We explore this process through the focused study of a pet dog, Teddy, who presented with six synchronous leiomyosarcomas. Using our pipeline we identified proteasome inhibitors as a potential therapy for Teddy. Teddy was treated with bortezomib and showed a varied response across tumors. Whole exome sequencing revealed substantial genetic heterogeneity across Teddy's recurrent tumors and metastases, suggesting that intra-patient heterogeneity and tumoral adaptation were responsible for the heterogeneous clinical response. Ubiquitin proteomics coupled with exome sequencing revealed multiple candidate driver mutations in proteins related to the proteasome pathway. Together, our results demonstrate how the comparative study of canine sarcomas offers important insights into the development of personalized medicine approaches that can lead to new treatments for sarcomas in both humans and canines.

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Blocking an N-terminal acetylation–dependent protein interaction inhibits an E3 ligase

Cited by 77 publications

References 60 publications

Co-translational, Post-translational, and Non-catalytic Roles of N-Terminal Acetyltransferases

Co-translational, Post-translational, and Non-catalytic Roles of N-Terminal Acetyltransferases

Squamous cell carcinoma–related oncogene (SCCRO) neddylates Cul3 protein to selectively promote midbody localization and activity of Cul3KLHL21 protein complex during abscission

From the Clinic to the Bench and Back Again in One Dog Year: How a Cross-Species Pipeline to Identify New Treatments for Sarcoma Illuminates the Path Forward in Precision Medicine

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