Structure of the MutLα C-terminal domain reveals how Mlh1 contributes to Pms1 endonuclease site
Structure of the MutLα C-terminal domain reveals how Mlh1 contributes to Pms1 endonuclease site
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DOI：
10.1038/nsmb.2511
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发表时间：
2013-04-01
影响因子：
16.8
通讯作者：
Charbonnier, Jean-Baptiste
中科院分区：
文献类型：
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作者：
Gueneau, Emeric;Dherin, Claudine;Charbonnier, Jean-Baptiste
错配修复因子在测量真核生物DNA复制保真度和确保正确的减数分裂重组中具有突出的作用。这些功能依赖于Mlh 1的MutL同源异二聚体。在人类中，MLH 1突变是一半遗传性非息肉病性结直肠癌（HNPCC）的基础。在这里，我们报告晶体结构的MutL α（Mlh 1-Pms 1异源二聚体）的C-末端结构域（CTD）从酿酒酵母，单独和复杂的片段来自Mlh 1的合作伙伴。这些结构揭示了MutL α中的结构重排和额外的结构域，与细菌MutL对应物相比，并表明Mlh 1的严格保守的C末端形成Pms 1内切核酸酶位点的一部分。MutL α（CTD）和exo 1或Ntg 2片段之间的三元复合物的结构揭示了几个Mlh 1伙伴共享的MIP-框基序的结合模式。最后，这些结构为MLH 1突变在HNPCC中的有害影响提供了理论依据。
Mismatch-repair factors have a prominent role in surveying eukaryotic DNA-replication fidelity and in ensuring correct meiotic recombination. These functions depend on MutL-homolog heterodimers with Mlh1. In humans, MLH1 mutations underlie half of hereditary nonpolyposis colorectal cancers (HNPCCs). Here we report crystal structures of the MutL alpha (Mlh1-Pms1 heterodimer) C-terminal domain (CTD) from Saccharomyces cerevisiae, alone and in complex with fragments derived from Mlh1 partners. These structures reveal structural rearrangements and additional domains in MutL alpha as compared to the bacterial MutL counterparts and show that the strictly conserved C terminus of Mlh1 forms part of the Pms1 endonuclease site. The structures of the ternary complexes between MutL alpha(CTD) and Exo1 or Ntg2 fragments reveal the binding mode of the MIP-box motif shared by several Mlh1 partners. Finally, the structures provide a rationale for the deleterious impact of MLH1 mutations in HNPCCs.