A small molecule antagonist of SMN disrupts the interaction between SMN and RNAP II

Liu, Yanli; Iqbal, Aman; Li, Weiguo; Ni, Zuyao; Wang, Yalong; Ramprasad, Jurupula; Abraham, Karan Joshua; Zhang, Mengmeng; Zhao, Dorothy Yanling; Su, Qin; Loppnau, P.; Jiang, Honglv; Guo, Xinghua; Brown, Peter J.; Zhen, Xuechu; Xu, Guoqiang; Mekhail, Karim; Ji, Xiangming; Bedford, Mark T.; Greenblatt, Jack; Min, Jinrong

doi:10.1038/s41467-022-33229-5

Cited by 12 publications

(9 citation statements)

References 58 publications

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“…In keeping with this observation, SMA-linked Tudor domain mutations prevent phase separation [ 53 ]. Elucidating the biological functions of SMN's methyl-reader ability will be facilitated now that a small molecule probe has been developed that selectively targets the Tudor domain of SMN [ 54 ].…”

Section: Tudor Domains As Methylarginine Readersmentioning

confidence: 99%

Effectors and effects of arginine methylation

Wang

Bedford

2023

Biochemical Society Transactions

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Arginine methylation is a ubiquitous and relatively stable post-translational modification (PTM) that occurs in three types: monomethylarginine (MMA), asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA). Methylarginine marks are catalyzed by members of the protein arginine methyltransferases (PRMTs) family of enzymes. Substrates for arginine methylation are found in most cellular compartments, with RNA-binding proteins forming the majority of PRMT targets. Arginine methylation often occurs in intrinsically disordered regions of proteins, which impacts biological processes like protein–protein interactions and phase separation, to modulate gene transcription, mRNA splicing and signal transduction. With regards to protein–protein interactions, the major ‘readers’ of methylarginine marks are Tudor domain-containing proteins, although additional domain types and unique protein folds have also recently been identified as methylarginine readers. Here, we will assess the current ‘state-of-the-art' in the arginine methylation reader field. We will focus on the biological functions of the Tudor domain-containing methylarginine readers and address other domains and complexes that sense methylarginine marks.

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Section: Tudor Domains As Methylarginine Readersmentioning

confidence: 99%

Effectors and effects of arginine methylation

Wang

Bedford

2023

Biochemical Society Transactions

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“…Indeed, most of them have considerable therapeutic potential. One subset of such compounds is the pyridin-4(1 H )-imines (Figure ), which has been explored as enzyme inhibitors (I) including, potentially, of antiplasmodial activity (II, III), as antimalarials (IV) and as selective antagonist agents (V) . Consequently, there is an attendant interest in the development of flexible, and efficient routes to synthesis of pyridin-4(1 H )-imines.…”

Section: Introductionmentioning

confidence: 99%

Chemoselectivity of the CuAAC/Ring Cleavage/Cyclization Reaction between Enaminones and α-Acylketenimine

Li,

Luo,

Luo

et al. 2024

J. Org. Chem.

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Ketenimines represent an important class of reactive species, useful synthetic intermediates, and synthons. However, in general, ketenimines preferentially undergoes nucleophilic addition reactions with hydroxyl and amino groups, and carbon functional groups remain a less studied subset of such systems. Herein, we develop a straightforward syntheses of pyridin-4(1H)-imines that is achieved by cyclization of a reacting enaminone unit with αacylketenimine which is generated from the reactions of sulfonyl azides and terminal ynones in situ (CuAAC/Ring cleavage reaction). The cascade process preferentially starts with the nucleophilic α-C of the enaminone unit instead of an amino group, attacking the electron-deficient central carbon of ketenimine, and the chemoselectivity unconventional products pyridin-4(1H)-imines were formed by intramolecular cyclization.

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“…SmEn facilitates cell lysate handling and protein purification by digesting genomic DNA to reduce lysate viscosity [2, 3]. It is also used to minimize nucleic acids carry-over for immunoblotting [4, 5], western blotting [3, 6], purifying viral vectors used for gene therapy, and sample preparation for 2D protein gels [7, 8]. Even though this reagent is commercially available from Millipore (as Benzonase ® ) and c-LECTA (as DENARASE ® ), it is expensive (more than $6000 per mg from Millipore) especially for large-scale lysate preparation.…”

Section: Introductionmentioning

confidence: 99%

Secretion and Periplasmic Activation of a Potent Endonuclease in E. coli

Soltani,

Swartz

2024

Preprint

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Sm Endonuclease (SmEn) is a promiscuous, highly active nuclease widely used in protein purification, 2D protein gels, and gene and cell therapy. We aimed to recombinantly and economically produce this reagent using E. coli. Despite widespread application of E. coli for recombinant production of proteins, cytoplasmic expression of this protein resulted in no activity accumulation. We therefore investigated translocation of SmEn to the periplasm of E. coli by evaluating several signal sequences, E. coli host cells, and incubation conditions. For rapid feedback, we developed a crude lysate-based nuclease activity assay that enabled convenient screening and identified suitable conditions for active SmEn accumulation. Signal sequence selection was most influential with additional benefit gained by slowing synthesis either using the transcriptionally weakened strain, C43 (DE3) or by reducing incubation temperature. While our study provides valuable insights for optimizing a nuclease translocation and reducing production costs, more research is needed to explore the influence of mRNA secondary structure at the translation initiation region on protein expression and translocation. Overall, our rapid screening assay facilitated the development of an effective production process for a protein with potential cytoplasmic toxicity as well as the need of disulfide bond formation.

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A small molecule antagonist of SMN disrupts the interaction between SMN and RNAP II

Cited by 12 publications

References 58 publications

Effectors and effects of arginine methylation

Effectors and effects of arginine methylation

Chemoselectivity of the CuAAC/Ring Cleavage/Cyclization Reaction between Enaminones and α-Acylketenimine

Secretion and Periplasmic Activation of a Potent Endonuclease in E. coli

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