Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation.
Kathleen M. Sakamoto,Kyung Bo Kim,Akiko Kumagai,Frank Mercurio,Craig M. Crews,Raymond J. Deshaies +5 more
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TLDR
It is shown that MetAP-2 can be tethered to SCFβ-TRCP, ubiquitinated, and degraded in a Protac-1-dependent manner, which may be useful for conditional inactivation of proteins, and for targeting disease-causing proteins for destruction.Abstract:
The intracellular levels of many proteins are regulated by ubiquitin-dependent proteolysis. One of the best-characterized enzymes that catalyzes the attachment of ubiquitin to proteins is a ubiquitin ligase complex, Skp1-Cullin-F box complex containing Hrt1 (SCF). We sought to artificially target a protein to the SCF complex for ubiquitination and degradation. To this end, we tested methionine aminopeptidase-2 (MetAP-2), which covalently binds the angiogenesis inhibitor ovalicin. A chimeric compound, protein-targeting chimeric molecule 1 (Protac-1), was synthesized to recruit MetAP-2 to SCF. One domain of Protac-1 contains the IκBα phosphopeptide that is recognized by the F-box protein β-TRCP, whereas the other domain is composed of ovalicin. We show that MetAP-2 can be tethered to SCFβ-TRCP, ubiquitinated, and degraded in a Protac-1-dependent manner. In the future, this approach may be useful for conditional inactivation of proteins, and for targeting disease-causing proteins for destruction.read more
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A Method for Conditional Regulation of Protein Stability in Native or Near-Native Form.
TL;DR: A method to regulate cellular protein levels by introducing a ubiquitin variant between a destabilizing domain (DD) and the regulated protein, which leads to higher expression levels of regulated protein when cells experience transient exposure to a stabilizing ligand.
Journal ArticleDOI
DeepPROTACs is a deep learning-based targeted degradation predictor for PROTACs
Fenglei Li,Qiaoyu Hu,Xianglei Zhang,Renhong Sun,Zhuanghua Liu,Sanan Wu,Siyuan Tian,Xinyue Ma,Zhizhuo Dai,Xiaobao Yang,Shenghua Gao,Fang Bai +11 more
TL;DR: In this article , a deep neural network model was proposed to predict the degradation capacity of a proposed PROTAC molecule based on structures of given target protein and E3 ligase, which achieved 77.95% average prediction accuracy and 0.8470 area under receiver operating characteristic curve on the test set.
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Exploring Methods of Targeting Histone Methyltransferases and Their Applications in Cancer Therapeutics.
TL;DR: The evolution of chemical approaches that have emerged in the past five years to design probes targeting HMTs are discussed, including inhibition through noncovalent inhibitors, covalent inhibitor, and targeted protein degradation through proteolysis targeting chimeras (PROTACs).
Journal ArticleDOI
Ubiquitination and SUMOylation of Amyloid and Amyloid-like Proteins in Health and Disease.
TL;DR: The functional contributions of PTMs on proteins involved in amyloid-related diseases as well as the aberrant PTM signatures of the disease agents are discussed, extending the discussion to the nascent field of functional amyloidal, a subclass of amyloids that perform physiological functions.
Journal ArticleDOI
The Role of Protein Engineering in Biomedical Applications of Mammalian Synthetic Biology
Daniel Bojar,Martin Fussenegger +1 more
TL;DR: Recent developments in protein engineering aided by advances in directed evolution, de novo design, and machine learning are discussed and are expected to further enhance the capabilities of mammalian synthetic biology in biomedical and other applications.
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