近日,，Genes&Development雜志報(bào)道,，研究者首次解析了磷酸化的Rb蛋白結(jié)構(gòu)，揭示了它失活的機(jī)制,。
細(xì)胞周期蛋白依賴激酶（Cdk）磷酸化視網(wǎng)膜神經(jīng)膠質(zhì)瘤蛋白（Rb）通過抑制Rb與E2F轉(zhuǎn)錄因子及其他調(diào)節(jié)蛋白形成復(fù)合體來驅(qū)動(dòng)細(xì)胞增殖。
研究發(fā)現(xiàn),，Rb 608位絲氨酸的磷酸化造成一個(gè)彈性的口袋狀結(jié)構(gòu)域環(huán),。該機(jī)構(gòu)模擬并直接阻斷E2F反式激活域(E2FTD)的結(jié)合。373位蘇氨酸的磷酸化誘導(dǎo)廣泛的口袋結(jié)構(gòu)和N末端結(jié)構(gòu)域（RbN）的構(gòu)象改變,。這個(gè)首次揭示的多結(jié)構(gòu)域Rb結(jié)構(gòu)證實(shí),，RbN在變構(gòu)抑制E2FTD-口袋結(jié)構(gòu)域結(jié)合以及蛋白與口袋結(jié)構(gòu)域特異位點(diǎn)的結(jié)合過程中發(fā)揮獨(dú)特的作用。
總之,，磷酸化的Rb蛋白結(jié)構(gòu)的破解為該經(jīng)典生長(zhǎng)-抑制復(fù)合體的調(diào)節(jié)機(jī)制提供了詳細(xì)信息,，并為了解多位點(diǎn)Cdk磷酸化如何誘導(dǎo)多結(jié)構(gòu)改變，進(jìn)而影響細(xì)胞周期信號(hào)通路提供了新的范例,。（生物谷Bioon.com)
doi:10.1016/j.cell.2011.10.017
Structures of inactive retinoblastoma protein reveal multiple mechanisms for cell cycle control
Jason R. Burke1, Greg L. Hura2 and Seth M. Rubin1,3
Cyclin-dependent kinase (Cdk) phosphorylation of the Retinoblastoma protein (Rb) drives cell proliferation through inhibition of Rb complexes with E2F transcription factors and other regulatory proteins. We present the first structures of phosphorylated Rb that reveal the mechanism of its inactivation. S608 phosphorylation orders a flexible “pocket” domain loop such that it mimics and directly blocks E2F transactivation domain (E2FTD) binding. T373 phosphorylation induces a global conformational change that associates the pocket and N-terminal domains (RbN). This first multidomain Rb structure demonstrates a novel role for RbN in allosterically inhibiting the E2FTD–pocket association and protein binding to the pocket “LxCxE” site. Together, these structures detail the regulatory mechanism for a canonical growth-repressive complex and provide a novel example of how multisite Cdk phosphorylation induces diverse structural changes to influence cell cycle signaling.
