Novel activity of KRAB domain that functions to reinforce nuclear localization of KRAB-containing zinc finger proteins by interacting with KAP1
Novel activity of KRAB domain that functions to reinforce nuclear localization of KRAB-containing zinc finger proteins by interacting with KAP1
复制标题
KRAB 结构域的新活性可通过与 KAP1 相互作用来增强含 KRAB 的锌指蛋白的核定位
DOI：
10.1007/s00018-013-1359-4
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发表时间：
2013-10-01
影响因子：
8
通讯作者：
Huang, Zan
中科院分区：
文献类型：
--
作者：
Wang, Wei;Cai, Jinyang;Huang, Zan
在此之前，我们发现znf268基因的两个亚型（ZNF268a和ZNF268b2，分别具有和不具有KRAB结构域）可能在正常上皮细胞和宫颈癌中发挥不同的作用。本研究进一步研究了KRAB结构域通过加强ZNF268a的核定位在一定程度上定义了功能差异。我们发现单独的KRAB的A-box保留了主要的特异性核定位活性。相比之下，单独的B-box不具有核定位活性，但显著增强了核定位活性。与A-box的关键功能一致，A-box中6个保守残基（V9、V11、F13、E16、E17和W18）的每个突变都显著破坏了核定位活性。此外，在另外7个含有KRAB的锌指蛋白（KRAB- zfps）中证实了KRAB独特的核定位活性，表明这是KRAB- zfps的普遍特征。最后，KRAB通过与其协同抑制因子KAP1的RBCC结构域相互作用发挥其独特的核定位活性。我们的研究结果揭示了一种新的机制，通过与KAP1相互作用，KRAB结构域加强了KRAB- zfps的核定位。我们的研究还表明，由于异常的选择性剪接，KRAB- zfps中KRAB结构域的丢失可能有助于致癌。
Previously, we found that two isoforms of theZNF268gene (ZNF268a and ZNF268b2, with and without the KRAB domain, respectively) might play distinct roles in normal epithelia and in cervical cancer. Here we further investigated that KRAB domain defined the function disparity in part by reinforcing nuclear localization of ZNF268a. We found that the A-box of KRAB alone retained major specific nuclear localization activity. In contrast, the B-box alone did not have nuclear localization activity but enhanced it significantly. Consistent with the critical function of the A-box, each mutation of six conserved residues (V9, V11, F13, E16, E17 and W18) in the A-box dramatically impaired nuclear localization activity. Furthermore, the unique nuclear localization activity of KRAB was verified in seven additional KRAB-containing zinc finger proteins (KRAB-ZFPs), suggesting that it is a universal feature of KRAB-ZFPs. Finally, KRAB exerted its unique nuclear localization activity by interacting with the RBCC domain of its corepressor KAP1. Our results have revealed a novel mechanism by which the KRAB domain reinforces nuclear localization of KRAB-ZFPs by interacting with KAP1. Our study also suggests that loss of the KRAB domain in KRAB-ZFPs due to aberrant alternative splicing might contribute to carcinogenesis.