Buffa Pietro, Manzella Livia, Consoli Maria Letizia, Messina Angelo, Vigneri Paolo
Department of Biomedical Sciences, Section of General Pathology, University of Catania, Catania, Italy.
Proteins. 2007 Apr 1;67(1):1-11. doi: 10.1002/prot.21161.
The ABL and ARG tyrosine kinases regulate many pivotal cellular processes and are implicated in the pathogenesis of several forms of leukemia. We have modelled the previously uncharacterized core domain (SH3-SH2-tyrosine kinase) and C-terminal actin-binding domain of ARG. We have also investigated the structural arrangement of the ABL and ARG Cap region and of the long multifunctional region located downstream of the tyrosine kinase domain. We report that the ARG core domain is homologous to the corresponding ABL region, therefore suggesting that ARG catalytic activity is likely regulated by the same SH3-SH2 clamp described for ABL. We also report that the Cap of both ABL and ARG is natively unfolded. Hence, biological events determining the folding of the Cap are critical to allow its interaction with the tyrosine kinase C-lobe. Furthermore, our results show that, with the exception of the C-terminal actin-binding domain, the entire region encoded by the ABL and ARG last exon is natively unfolded. Phosphorylation events or protein-protein interactions regulating the folding of this region will therefore modulate the activity of its numerous functional domains. Finally, our analyses show that the C-terminal actin-binding domain of ARG displays a four-helix bundle structure similar to the one reported for the corresponding ABL region. Our findings imply that many biological activities attributed to ABL, ARG, and their oncogenic counterparts are regulated by natively unfolded regions.
ABL和ARG酪氨酸激酶调节许多关键的细胞过程，并与多种形式白血病的发病机制有关。我们对ARG先前未被表征的核心结构域（SH3-SH2-酪氨酸激酶）和C端肌动蛋白结合结构域进行了建模。我们还研究了ABL和ARG帽区以及位于酪氨酸激酶结构域下游的长多功能区域的结构排列。我们报告称，ARG核心结构域与相应的ABL区域同源，因此表明ARG催化活性可能受与ABL相同的SH3-SH2钳制调节。我们还报告称，ABL和ARG的帽区天然未折叠。因此，决定帽区折叠的生物学事件对于使其与酪氨酸激酶C叶相互作用至关重要。此外，我们的结果表明，除了C端肌动蛋白结合结构域之外，ABL和ARG最后一个外显子编码的整个区域天然未折叠。因此，调节该区域折叠的磷酸化事件或蛋白质-蛋白质相互作用将调节其众多功能结构域的活性。最后，我们的分析表明，ARG的C端肌动蛋白结合结构域呈现出与报道的相应ABL区域相似的四螺旋束结构。我们的研究结果表明，许多归因于ABL、ARG及其致癌对应物的生物学活性受天然未折叠区域的调节。
