Identification of a Novel LXXLL Motif in α-Actinin 4-spliced Isoform That Is Critical for Its Interaction with Estrogen Receptor α and Co-activators
Identification of a Novel LXXLL Motif in α-Actinin 4-spliced Isoform That Is Critical for Its Interaction with Estrogen Receptor α and Co-activators
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DOI：
10.1074/jbc.m112.401364
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发表时间：
2012-10-12
影响因子：
4.8
通讯作者：
Kao, Hung-Ying
中科院分区：
文献类型：
--
作者：
Khurana, Simran;Chakraborty, Sharmistha;Kao, Hung-Ying
α-Actinins(ACTN)是一类蛋白质家族，具有交联型肌动蛋白细丝，维持细胞骨架组织和细胞运动。最近，ACTN4在细胞核中的功能也变得清晰起来。在本报告中，我们发现ACTN4(全长)及其剪接的异构体ACTN4(Iso)具有一个不寻常的LxxL1核受体相互作用基序。ACTN4(全长)和ACTN4(Iso)都增强基础转录活性，并直接与雌激素受体α相互作用，尽管ACTN4(Iso)与ERα结合更强。我们还发现ACTN4(全长)和ACTN4(Iso)都与雌激素受体α的配体非依赖和配体依赖的激活域相互作用。虽然ACTN4(Iso)与转录共激活物如p300/CBP相关因子(PCAF)和类固醇受体共激活剂1(SRC-1)有效地相互作用，但全长ACTN4蛋白不能或很弱地与之相互作用。更重要的是，LxxLL基序的侧翼序列不仅对于与核受体的相互作用，而且对于与辅助激活子的结合都是重要的。综上所述，我们已经确定了一个新的扩展的LxxLL基序，它对与受体和辅助激活剂的相互作用至关重要。这个基序在ACTN4的剪接异构体中比在全长蛋白中更有效地发挥作用。
alpha-Actinins (ACTNs) are a family of proteins cross-linking actin filaments that maintain cytoskeletal organization and cell motility. Recently, it has also become clear that ACTN4 can function in the nucleus. In this report, we found that ACTN4 (full length) and its spliced isoform ACTN4 (Iso) possess an unusual LXXLL nuclear receptor interacting motif. Both ACTN4 (full length) and ACTN4 (Iso) potentiate basal transcription activity and directly interact with estrogen receptor alpha, although ACTN4 (Iso) binds ER alpha more strongly. We have also found that both ACTN4 (full length) and ACTN4 (Iso) interact with the ligand-independent and the ligand-dependent activation domains of estrogen receptor alpha. Although ACTN4 (Iso) interacts efficiently with transcriptional co-activators such as p300/CBP-associated factor (PCAF) and steroid receptor co-activator 1 (SRC-1), the full length ACTN4 protein either does not or does so weakly. More importantly, the flanking sequences of the LXXLL motif are important not only for interacting with nuclear receptors but also for the association with co-activators. Taken together, we have identified a novel extended LXXLL motif that is critical for interactions with both receptors and co-activators. This motif functions more efficiently in a spliced isoform of ACTN4 than it does in the full-length protein.