VIB-VUB Center for Structural Biology, Pleinlaan 2, 1050, Brussels, Belgium.
Structural Biology Brussels, Department of Bioengineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, 1050, Brussels, Belgium.
Commun Biol. 2022 May 11;5(1):445. doi: 10.1038/s42003-022-03391-z.
Effective organization of proteins into functional modules (networks, pathways) requires systems-level coordination between transcription, translation and degradation. Whereas the cooperation between transcription and translation was extensively studied, the cooperative degradation regulation of protein complexes and pathways has not been systematically assessed. Here we comprehensively analyzed degron masking, a major mechanism by which cellular systems coordinate degron recognition and protein degradation. For over 200 substrates with characterized degrons (E3 ligase targeting motifs, ubiquitination sites and disordered proteasomal entry sequences), we demonstrate that degrons extensively overlap with protein-protein interaction sites. Analysis of binding site information and protein abundance comparisons show that regulatory partners effectively outcompete E3 ligases, masking degrons from the ubiquitination machinery. Protein abundance variations between normal and cancer cells highlight the dynamics of degron masking components. Finally, integrative analysis of gene co-expression, half-life correlations and functional relationships between interacting proteins point towards higher-order, co-regulated degradation modules ('degronons') in the proteome.
有效的蛋白质功能模块（网络、途径）组织需要转录、翻译和降解之间的系统水平协调。虽然转录和翻译之间的合作已经得到了广泛的研究，但蛋白质复合物和途径的协同降解调节尚未得到系统评估。在这里，我们全面分析了去屏蔽（degron masking），这是细胞系统协调去屏蔽识别和蛋白质降解的主要机制。对于 200 多个具有特征性去屏蔽（E3 连接酶靶向基序、泛素化位点和无序蛋白酶体进入序列）的底物，我们证明去屏蔽广泛重叠于蛋白质-蛋白质相互作用位点。结合位点信息分析和蛋白质丰度比较表明，调节伙伴有效地与 E3 连接酶竞争，使去屏蔽免受泛素化机制的影响。正常细胞和癌细胞之间的蛋白质丰度变化突出了去屏蔽组件的动态变化。最后，对相互作用蛋白的基因共表达、半衰期相关性和功能关系的综合分析表明，蛋白质组中存在更高阶、共同调节的降解模块（“degronons”）。
