KLHL40

3月20日，来自多伦多大学的科学家团队在Nature杂志发表重要论文。研究者们创建了一个新的平台，访问了整个人类蛋白质组，以鉴定能够影响其他蛋白质稳定性的“效应蛋白（effector proteins）”。该研究是科学家们首次在这种规模级别寻找“效应蛋白”，且发现了许多可用于蛋白降解剂、蛋白稳定剂开发的新“效应蛋白”。来源：Nature具体来说，该研究在14000个基因中发现了600多种新的效应蛋白。超过200种新的效应蛋白能够有效地降解目标蛋白，而大约400种效应蛋白能够稳定目标蛋白。人类E3连接酶作为邻近依赖降解剂的功能评估（来源：Nature）目前用于靶向蛋白降解和稳定的效应蛋白分别是E3泛素连接酶（E3 ubiquitin-ligases）和去泛素酶（deubiquitinases）。在细胞中，E3泛素连接酶可通过将一种叫做泛素的小蛋白贴在靶蛋白上将其标记为缺陷或受损蛋白。之后，细胞内的蛋白粉碎机（即蛋白酶体）会处理掉被标记的靶蛋白。相反的，去泛素酶从蛋白质上去除泛素标签，从而防止蛋白质被蛋白酶体识别和降解。这项最新研究发现，不同E3泛素连接酶降解与之接触的靶蛋白的程度有很大的不同。研究小组甚至发现了4种“超强E3泛素连接酶”（angry E3），这些E3泛素连接酶不受其它因素（如目标蛋白在细胞中的位置）的影响，始终能降解目标蛋白。一个特别令人惊讶的发现是，一些用于靶向蛋白降解的最强效应器，是E2偶联酶（E2 conjugating enzymes），而不是E3连接酶。它们与E3连接酶的不同之处在于，它们参与蛋白质降解的早期步骤，而不是直接engage靶蛋白。由于E2连接酶不被认为容易成药，它们直到最近才被用于靶向蛋白降解。这项研究揭示了E2连接酶这类更强的效应器未被开发的潜力。E2偶联酶UBE2B是一种有效的邻近依赖性降解剂（来源：Nature）该研究还揭示，效应器KLHL40可能被用于开发靶向蛋白稳定剂，以治疗骨骼肌疾病。效应器FBXL12和FBXL15介导的靶向蛋白降解可能用于治疗慢性髓系白血病。KLHL40是一种有效的蛋白稳定效应器（来源：Nature）“通过诱导接近（induced proximity）来靶向蛋白质是一个新的有前途的生物医学研究领域。我们的研究发现了大量新的效应蛋白，这些蛋白值得进一步探索用于新药研发的潜力。”领导该研究的分子遗传学副教授Mikko Taipale说道。推荐阅读：跨界了！David Liu最新Science，关于“分子胶”参考资料：[1]https://www-nature-com.libproxy1.nus.edu.sg/articles/s41586-024-07224-3[2]https://thedonnellycentre.utoronto.ca/news/toronto-researchers-devise-new-method-find-proteins-targeted-treatment-diseaseCopyright © 2023 PHARMCUBE. All Rights Reserved.欢迎转发分享及合理引用，引用时请在显要位置标明文章来源；如需转载，请给微信公众号后台留言或发送消息，并注明公众号名称及ID。免责申明：本微信文章中的信息仅供一般参考之用，不可直接作为决策内容，医药魔方不对任何主体因使用本文内容而导致的任何损失承担责任。精彩预告线上直播&线下会议↑ 点击扫码，报名参会 ↑

Researchers have created a new platform to identify proteins that can be co-opted to control the stability of other proteins -- a new but largely unrealized approach to the treatment of disease. Researchers at the University of Toronto and Sinai Health have created a new platform to identify proteins that can be co-opted to control the stability of other proteins -- a new but largely unrealized approach to the treatment of disease. The researchers developed a method to interrogate the entire human proteome for 'effector' proteins, which can influence the stability of other proteins via induced proximity. The study marks the first time researchers have searched for effector proteins on this scale, and has identified many new effectors that could be used therapeutically. "We found more than 600 new effector proteins in 14,000 genes," said Juline Poirson, first author on the study and visiting scientist at U of T's Donnelly Centre for Cellular and Biomolecular Research. "Over 200 of the new effectors can efficiently degrade their target proteins, while about 400 effectors were capable of stabilizing, and thereby increasing the abundance of, an artificial target protein." The study, which involved researchers at Sinai Health's Lunenfeld-Tanenbaum Research Institute, was published in the journal Nature. "Targeting proteins through induced proximity is a new and promising area of biomedical research," said Mikko Taipale, principal investigator on the study and an associate professor of molecular genetics at the Donnelly Centre and the Temerty Faculty of Medicine. "Not only did we find new effectors worth further investigation for drug discovery, we developed a synthetic platform that can be used to conduct unbiased, proteome-wide, induced-proximity screens to continue expanding the library of effector proteins." The effectors currently in use for targeted protein degradation and stabilization are E3 ubiquitin-ligases (E3s) and deubiquitinases (DUBs), respectively. E3 is an enzyme that transfers the ubiquitin molecule to the target protein, which essentially flags the protein for a proteosome to digest it. On the other hand, a DUB enzyme removes the ubiquitin tag from a protein, thereby preventing the protein from being recognized and degraded by a proteosome. The results of the study demonstrate that E3s are quite varied in the degree to which they can degrade target proteins they are brought into contact with. The research team even discovered four of what they call 'angry E3s,' which consistently degrade targets regardless of other factors, such as the location of the target within the cell. A particularly surprising finding was that some of the strongest effectors for targeted protein degradation were E2 conjugating enzymes, instead of E3s. These differ from E3s in that they are involved at an earlier step of protein degradation and do not directly engage the target protein. Because E2s were not considered to be easily druggable, they had not been harnessed for targeted protein degradation until recently. They represent, however, the untapped potential of stronger effectors than ones currently in use. The study shows that exploring the whole proteome for induced proximity offers enormous opportunities for therapeutic interventions. KLHL40, one of the identified effectors, could potentially be hijacked for targeted protein stabilization to treat skeletal muscle disorders. The research team also found that targeted protein degradation with FBXL12 and FBXL15 effectors could be particularly useful in treating chronic myeloid leukemia. Targeted protein degradation and stabilization are innovative methods of drug discovery that have thus far been plagued with the "protein pair problem," where the best effector for a target protein cannot be predicted accurately. Matching a target protein with the right effector is essential to successfully, and safely, facilitate degradation and stabilization processes in tissues. "The synthetic screening platform developed by our team solves the protein matching issue through rapid, large-scale testing of effector and target protein interactions," said Poirson. "We're confident that an unbiased induced-proximity approach can be used to find effectors for almost any target."