Characterization of the APLF FHA-XRCC1 phosphopeptide interaction and its structural and functional implications.
Characterization of the APLF FHA-XRCC1 phosphopeptide interaction and its structural and functional implications.
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DOI：
10.1093/nar/gkx941
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发表时间：
2017-12-01
影响因子：
14.9
通讯作者：
London RE
中科院分区：
文献类型：
--
作者：
Kim K;Pedersen LC;Kirby TW;DeRose EF;London RE
Aprataxin和PNKP样因子（APLF）是一种DNA修复因子，含有叉头相关（FHA）结构域，支持与XRCC 1和XRCC 4中磷酸化FHA结构域结合基序（FBM）结合。我们的特点是相互作用的APLF FHA结构域与磷酸化XRCC 1肽使用晶体学，NMR和荧光偏振研究。的FHA-FBM相互作用表现出显着的pH值的依赖性，在生理范围内的结果的高pK值的磷酸丝氨酸和磷酸苏氨酸残基和FHA结合的pThr的双阴离子电荷状态的偏好。这些高pK值是通常由CK 2磷酸化产生的聚阴离子肽的特征。晶体学定义的识别基序侧翼的残基极大地增强了结合亲和力，显然是非特异性静电相互作用的结果，支持XRCC 1在APLF核共转运中的作用。XRCC 1与APLF的FHA结构域依赖性相互作用连接支持单链断裂修复和非同源末端连接（NHEJ）的修复支架。这表明，对于最初与PARP 1及其结合伴侣XRCC 1形成复合物的双链DNA断裂，这种相互作用通过招募Ku和相关的NHEJ因子作为拦截更容易出错的替代NHEJ修复途径的备份尝试。
Aprataxin and PNKP-like factor (APLF) is a DNA repair factor containing a forkhead-associated (FHA) domain that supports binding to the phosphorylated FHA domain binding motifs (FBMs) in XRCC1 and XRCC4. We have characterized the interaction of the APLF FHA domain with phosphorylated XRCC1 peptides using crystallographic, NMR, and fluorescence polarization studies. The FHA–FBM interactions exhibit significant pH dependence in the physiological range as a consequence of the atypically high pK values of the phosphoserine and phosphothreonine residues and the preference for a dianionic charge state of FHA-bound pThr. These high pK values are characteristic of the polyanionic peptides typically produced by CK2 phosphorylation. Binding affinity is greatly enhanced by residues flanking the crystallographically-defined recognition motif, apparently as a consequence of non-specific electrostatic interactions, supporting the role of XRCC1 in nuclear cotransport of APLF. The FHA domain-dependent interaction of XRCC1 with APLF joins repair scaffolds that support single-strand break repair and non-homologous end joining (NHEJ). It is suggested that for double-strand DNA breaks that have initially formed a complex with PARP1 and its binding partner XRCC1, this interaction acts as a backup attempt to intercept the more error-prone alternative NHEJ repair pathway by recruiting Ku and associated NHEJ factors.
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影响因子：
14.9
作者：
Hanzlikova H;Gittens W;Krejcikova K;Zeng Z;Caldecott KW
通讯作者：
Caldecott KW
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
3.4
作者：
JAYANTH, VR;BAYNE, MT;VARNES, ME
通讯作者：
VARNES, ME
影响因子：
4.8
作者：
Cappelli, E;Taylor, R;Frosina, G
通讯作者：
Frosina, G
影响因子：
16.6
作者：
Kazimierczuk, Krzysztof;Orekhov, Vladislav Yu.
通讯作者：
Orekhov, Vladislav Yu.