加拿大多伦多大学Mikko Taipale课题组从蛋白质组规模发现蛋白质降解和稳定的效应蛋白。相关论文于2024年3月20日在线发表在《自然》杂志上。

研究人员建立了一个合成蛋白质组规模的平台，从功能上鉴定能以接近依赖的方式促进靶蛋白降解或稳定的人类蛋白质。研究结果表明，人类蛋白质组含有大量的蛋白质稳定性效应蛋白。这种方法进一步使研究人员能够全面比较人类E3连接酶和去泛素化酶的活性，识别非经典蛋白质降解剂和稳定剂并确定其特征，同时确定效应蛋白针对不同靶标的活性存在巨大差异。

值得注意的是，与目前使用的E3连接酶cereblon和VHL相比，最好的降解蛋白对多个治疗相关靶点的作用更强。该研究为靶向蛋白质降解和稳定提供了稳定性效应蛋白的功能目录，并突出了诱导性近距离筛选在发现新的近距离依赖性蛋白质调节因子方面的潜力。

据了解，靶向蛋白质降解和稳定是一种很有前景的治疗方式，因为它们具有强效性、多功能性以及扩大药物靶点空间的潜力。然而，在人类蛋白质组的数百种E3连接酶和去泛素酶中，只有少数几种被用于这一目的，这大大限制了这种方法的潜力。此外，可能还有其他蛋白质类别可用于稳定或降解蛋白质，但目前还没有一种方法能以可扩展和无偏倚的方式识别这类效应蛋白。

附：英文原文

Title: Proteome-scale discovery of protein degradation and stabilization effectors

Author: Poirson, Juline, Cho, Hanna, Dhillon, Akashdeep, Haider, Shahan, Imrit, Ahmad Zoheyr, Lam, Mandy Hiu Yi, Alerasool, Nader, Lacoste, Jessica, Mizan, Lamisa, Wong, Cassandra, Gingras, Anne-Claude, Schramek, Daniel, Taipale, Mikko

Issue&Volume: 2024-03-20

Abstract: Targeted protein degradation and stabilization are promising therapeutic modalities because of their potency, versatility and their potential to expand the druggable target space1,2. However, only a few of the hundreds of E3 ligases and deubiquitinases in the human proteome have been harnessed for this purpose, which substantially limits the potential of the approach. Moreover, there may be other protein classes that could be exploited for protein stabilization or degradation3,4,5, but there are currently no methods that can identify such effector proteins in a scalable and unbiased manner. Here we established a synthetic proteome-scale platform to functionally identify human proteins that can promote the degradation or stabilization of a target protein in a proximity-dependent manner. Our results reveal that the human proteome contains a large cache of effectors of protein stability. The approach further enabled us to comprehensively compare the activities of human E3 ligases and deubiquitinases, identify and characterize non-canonical protein degraders and stabilizers and establish that effectors have vastly different activities against diverse targets. Notably, the top degraders were more potent against multiple therapeutically relevant targets than the currently used E3 ligases cereblon and VHL. Our study provides a functional catalogue of stability effectors for targeted protein degradation and stabilization and highlights the potential of induced proximity screens for the discovery of new proximity-dependent protein modulators.

DOI: 10.1038/s41586-024-07224-3

Source: https://www.nature.com/articles/s41586-024-07224-3