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Interaction between the scaffold proteins CBP by IQGAP1 provides an interface between gene expression and cytoskeletal activity.
Scientific Reports ( IF 4.6 ) Pub Date : 2020-04-01 , DOI: 10.1038/s41598-020-62069-w
Simone Kosol 1, 2 , Sara Contreras-Martos 1, 2 , Alessandro Piai 3, 4 , Mihaly Varadi 1, 2 , Tamas Lazar 1, 2 , Angela Bekesi 1, 2 , Pierre Lebrun 1, 2 , Isabella C Felli 3, 4 , Roberta Pierattelli 3, 4 , Peter Tompa 1, 2, 5
Affiliation  

Crosstalk between cellular pathways is often mediated through scaffold proteins that function as platforms for the assembly of signaling complexes. Based on yeast two-hybrid analysis, we report here the interaction between two complex scaffold proteins, CREB-binding protein (CBP) and the Ras GTPase-activating-like protein 1 (IQGAP1). Dissection of the interaction between the two proteins reveals that the central, thus far uncharacterized, region of IQGAP1 interacts with the HAT domain and the C-terminal intrinsically disordered region of CBP (termed ID5). Structural analysis of ID5 by solution NMR spectroscopy and SAXS reveals the presence of two regions with pronounced helical propensity. The ID5 region(s) involved in the interaction of nanomolar affinity were delineated by solution NMR titrations and pull-down assays. Moreover, we found that IQGAP1 acts as an inhibitor of the histone acetyltransferase (HAT) activity of CBP. In in vitro assays, the CBP-binding region of IQGAP1 positively and negatively regulates the function of HAT proteins of different families including CBP, KAT5 and PCAF. As many signaling pathways converge on CBP and IQGAP1, their interaction provides an interface between transcription regulation and the coordination of cytoskeleton. Disruption or alteration of the interaction between these scaffold proteins may lead to cancer development or metastatic processes, highlighting the importance of this interaction.



中文翻译:

IQGAP1在支架蛋白CBP之间的相互作用提供了基因表达与细胞骨架活性之间的接口。

细胞途径之间的串扰通常是通过支架蛋白介导的,而支架蛋白起着信号复合体组装平台的作用。基于酵母双杂交分析,我们在这里报告了两个复杂支架蛋白,CREB结合蛋白(CBP)和Ras GTPase激活样蛋白1(IQGAP1)之间的相互作用。两种蛋白质之间相互作用的解剖揭示,IQGAP1的中央区域(迄今尚未表征)与HAT域和CBP的C端固有无序区域(称为ID5)相互作用。通过溶液NMR光谱和SAXS对ID5进行结构分析,发现存在两个具有明显螺旋倾向的区域。通过溶液NMR滴定和下拉测定法确定了与纳摩尔亲和力相互作用有关的ID5区。此外,我们发现IQGAP1可以抑制CBP的组蛋白乙酰转移酶(HAT)活性。在在体外试验中,IQGAP1的CBP结合区正向和负向调节包括CBP,KAT5和PCAF在内的不同家族的HAT蛋白的功能。由于许多信号通路在CBP和IQGAP1上汇合,因此它们的相互作用为转录调节和细胞骨架的协调提供了接口。这些支架蛋白之间相互作用的破坏或改变可能导致癌症发展或转移过程,从而突出了这种相互作用的重要性。

更新日期:2020-04-01
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