Internal regulatory interactions determine DNA binding specificity by a Hox transcription factor.
Internal regulatory interactions determine DNA binding specificity by a Hox transcription factor.
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DOI：
10.1016/j.jmb.2009.05.059
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发表时间：
2009-07-24
影响因子：
5.6
通讯作者：
Bondos, Sarah E.
中科院分区：
文献类型：
--
作者：
Liu, Ying;Matthews, Kathleen S.;Bondos, Sarah E.
在发育中，Hox转录因子家族调节下游基因的电池以使连续重复单元多样化。考虑到Hox同源结构域在体外结合的DNA结合位点比在体内由全长蛋白质调节的DNA结合位点更广泛，同源结构域以外的区域必须有助于DNA位点选择。事实上，我们发现不同的DNA序列的亲和力变化小于3倍的同源结构域分离的果蝇Hox蛋白Ultrabithorax Ia（UbxHD），而全长蛋白（UbxIa）的亲和力相差超过10倍。优选的DNA序列的排序也不同，进一步证明了不同的DNA结合偏好。UbxIa的特异性增强部分归因于I1区域，该区域邻近同源结构域并直接影响结合能量学。I1内的三个片段中的每一个-齿外结合YPWM基序、紧邻该基序N末端的6个氨基酸和邻接YPWM C末端的8个氨基酸-独特地贡献于DNA特异性。这些区域的组合协同修饰DNA结合以进一步增强特异性。有趣的是，UbxIa中YPWM基序的存在仅抑制DNA与Ubx·Extradenticle异源二聚体结合位点的结合，可能在体内起作用以防止Ubx单体结合和误调节异源二聚体靶基因。然而，去除周围区域允许YPWM基序也抑制与仅Hox识别序列的结合。尽管Hox蛋白的模块化结构域设计，这些结果表明，多个Hox蛋白区域形成了一个网络的监管相互作用，协调上下文和基因特异性的反应。由于大多数非同源结构域区域在Hox家族成员之间不保守，这些调节相互作用具有通过高度同源的Hox同源结构域使结合多样化的潜力。
In developing bilaterans, the Hox transcription factor family regulates batteries of downstream genes to diversify serially repeated units. Given Hox homeodomains bind a wider array of DNA binding sites in vitro than are regulated by the full-length protein in vivo, regions outside the homeodomain must aid DNA site selection. Indeed, we find affinity for disparate DNA sequences varies less than 3-fold for the homeodomain isolated from the Drosophila Hox protein Ultrabithorax Ia (UbxHD), whereas for the full-length protein (UbxIa) affinity differs by more than 10-fold. The rank order of preferred DNA sequences also differs, further demonstrating distinct DNA binding preferences. The increased specificity of UbxIa can be partially attributed to the I1 region, which lies adjacent to the homeodomain and directly impacts binding energetics. Each of three segments within I1 – the Extradenticle-binding YPWM motif, the 6 amino acids immediately N-terminal to this motif, and the 8 amino acids abutting the YPWM C-terminus – uniquely contribute to DNA specificity. Combination of these regions synergistically modifies DNA binding to further enhance specificity. Intriguingly, the presence of the YPWM motif in UbxIa inhibits DNA binding only to Ubx•Extradenticle heterodimer binding sites, potentially functioning in vivo to prevent Ubx monomers from binding and misregulating heterodimer target genes. However, removal of the surrounding region allows the YPWM motif to also inhibit binding to Hox-only recognition sequences. Despite a modular domain design for Hox proteins, these results suggest that multiple Hox protein regions form a network of regulatory interactions that coordinate context-and gene-specific responses. Since most non-homeodomain regions are not conserved between Hox family members, these regulatory interactions have the potential to diversify binding by the highly homologous Hox homeodomains.
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影响因子：
7
作者：
Bondos, SE;Tan, XX;Matthews, KS
通讯作者：
Matthews, KS
DOI：
10.1073/pnas.90.13.6360
发表时间：
1993-07-01
影响因子：
11.1
作者：
FURUKUBOTOKUNAGA, K;FLISTER, S;GEHRING, WJ
通讯作者：
GEHRING, WJ
影响因子：
64.5
作者：
Berger, Michael F.;Badis, Gwenael;Hughes, Timothy R.
通讯作者：
Hughes, Timothy R.
影响因子：
11.8
作者：
Gebelein, B;Culi, J;Mann, RS
通讯作者：
Mann, RS
影响因子：
2.9
作者：
Bondos, SE;Bicknell, A
通讯作者：
Bicknell, A