Cooperativity within proximal phosphorylation sites is revealed from large-scale proteomics data.
Cooperativity within proximal phosphorylation sites is revealed from large-scale proteomics data.
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DOI：
10.1186/1745-6150-5-6
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发表时间：
2010-01-26
期刊：
影响因子：
5.5
通讯作者：
Linial M
中科院分区：
文献类型：
--
作者：
Schweiger R;Linial M
磷酸化是真核蛋白质最普遍的翻译后修饰。多位点磷酸化使特定的亚磷酸盐组合能够决定生物反应的速度、特异性和持续时间。直到最近几年，缺乏高质量的数据限制了在蛋白质组水平和在广泛条件下分析磷酸化性质的可能性。由于质谱学技术的进步，数以千计的来自体内实验的磷酸盐被鉴定出来，并在公共领域存档。这种资源适合于对真核生物中的亚磷酸盐性质及其功能相关性得出公正的观点。我们对大约70,000个已报道的亚磷酸盐集合的空间和功能特性进行了严格的统计测试。我们发现，沿着蛋白质定位的亚磷酸盐倾向于以密集的丝氨酸/苏氨酸(PS/PT)簇的形式出现，并出现在丝氨酸/苏氨酸和酪氨酸之间，但通常不太多，只出现在酪氨酸(Py)之间。这种现象比预期的更普遍，而且与大多数真核蛋白质有关：对于带有≥2亚磷酸的蛋白质，54%的PS/PT位点位于另一个位点的4个氨基酸以内。我们发现聚集性PS/PT有被相同的激酶激活的强烈倾向。因此，对磷酸肽的大规模分析与集群内的合作功能是一致的。我们提出的证据支持这一观点，即PS/PT簇而不是Py簇应该被认为是磷酸化调控的基本构件。事实上，位置接近的位置往往被相同的激酶激活，这一信号推翻了蛋白质被单一或仅由几个激酶激活的倾向。在这些集群中，协调和位置依赖是显而易见的。我们假设细胞调节利用了这种设计。具体地说，亚磷酸盐簇可以增加磷酸化依赖反应有效性的稳健性。作者：Joel Bader，Frank Eisenhaber，Emmanuel Levy(Sarah Teichmann提名)。要获得完整的评论，请转到评论者评论部分。
Phosphorylation is the most prevalent post-translational modification on eukaryotic proteins. Multisite phosphorylation enables a specific combination of phosphosites to determine the speed, specificity and duration of biological response. Until recent years, the lack of high quality data limited the possibility for analyzing the properties of phosphorylation at the proteome scale and in the context of a wide range of conditions. Thanks to advances of mass spectrometry technologies, thousands of phosphosites from in-vivo experiments were identified and archived in the public domain. Such resource is appropriate to derive an unbiased view on the phosphosites properties in eukaryotes and on their functional relevance. We present statistically rigorous tests on the spatial and functional properties of a collection of ~70,000 reported phosphosites. We show that the distribution of phosphosites positioning along the protein tends to occur as dense clusters of Serine/Threonines (pS/pT) and between Serine/Threonines and Tyrosines, but generally not as much between Tyrosines (pY) only. This phenomenon is more ubiquitous than anticipated and is pertinent for most eukaryotic proteins: for proteins with ≥ 2 phosphosites, 54% of all pS/pT sites are within 4 amino acids of another site. We found a strong tendency for clustered pS/pT to be activated by the same kinase. Large-scale analyses of phosphopeptides are thus consistent with a cooperative function within the cluster. We present evidence supporting the notion that clusters of pS/pT but generally not pY should be considered as the elementary building blocks in phosphorylation regulation. Indeed, closely positioned sites tend to be activated by the same kinase, a signal that overrides the tendency of a protein to be activated by a single or only few kinases. Within these clusters, coordination and positional dependency is evident. We postulate that cellular regulation takes advantage of such design. Specifically, phosphosite clusters may increase the robustness of the effectiveness of phosphorylation-dependent response. Reviewed by Joel Bader, Frank Eisenhaber, Emmanuel Levy (nominated by Sarah Teichmann). For the full reviews, please go to the Reviewers' comments section.
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