DNA错配修复在保证DNA复制的忠实性方面发挥重要作用，Multα是真核生物错配修复过程中的重要蛋白质，它和其它蛋白质的相互作用可能由其构象变化所调节。Sacho等人用原子力显微镜直接观察到了Mutlα的构象变化，该研究结果以封面文章的形式发表在1月18日的《分子细胞》上。
Multα是原核生物中Mult的同源蛋白质，是由Mlh1和Pms2（酵母中为Pms1）构成的异源双聚体，每个单体均包括一个C末端二聚体结构域和N末端ATP酶结构域。Mutl及其同源体属于GHL ATP酶家族，该家族的蛋白质会由于ATP的结合或（和）水解发生构象变化，这和细胞中信号转导途径相关。
以往研究表明ATP的结合可能导致Mutlα的构象变化，并由此调节其于其它蛋白质的相互作用，激活下游的蛋白因子启动DNA错配修复过程，但这些推断仅源于对分离的蛋白质部分结构域的晶体衍射和尺寸排阻色谱以及间接的生物化学分析，缺乏直接的证据。
来自美国北卡罗来纳大学等多家研究机构的科学家用原子力显微镜观测了酵母和人类Multα整个分子的构象，结果发现二者均存在四种构象，ATP和ADP的结合均能够改变其构象。用部分水解等生物化学分析方法，发现在溶液中ATP的结合也能够改变Multα的构象。该构象变化涉及大量二级结构的改变。
为检测Multα构象变化是否必需ATP的水解，研究人员进一步对缺乏ATP水解酶活性的Multα突变体进行研究，并且用不可水解的ATP同源物AMPPNP做比较研究，结果表明ATP构象变化是由ATP的结合所引起，而非ATP水解。
据推测，Multα的四种构想可能和ATP的结合、水解和释放过程相关，Multα通过构象变化暴露或隐藏部分结构，从而改变同其它蛋白质间的相互作用。（科学网 穆宏平/编译）
（《分子细胞》（Molecular Cell），Vol 29, 112-121, 18 January 2008，Elizabeth J. Sacho, Dorothy A. Erie）
生物谷推荐英文原文：
Molecular Cell, Vol 29, 112-121, 18 January 2008
Article
Direct Visualization of Asymmetric Adenine Nucleotide-Induced Conformational Changes in MutLα
Elizabeth J. Sacho,1 Farid A. Kadyrov,4 Paul Modrich,3,4 Thomas A. Kunkel,5 and Dorothy A. Erie1,2,
1 Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
2 Curriculum in Applied and Materials Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
3 Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA
4 Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, USA
5 Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA
Corresponding author
Dorothy A. Erie
derie@unc.edu
MutLα, the heterodimeric eukaryotic MutL homolog, is required for DNA mismatch repair (MMR) in vivo. It has been suggested that conformational changes, modulated by adenine nucleotides, mediate the interactions of MutLα with other proteins in the MMR pathway, coordinating the recognition of DNA mismatches by MutSα and the activation of MutLα with the downstream events that lead to repair. Thus far, the only evidence for these conformational changes has come from X-ray crystallography of isolated domains, indirect biochemical analyses, and comparison to other members of the GHL ATPase family to which MutLα belongs. Using atomic force microscopy (AFM), coupled with biochemical techniques, we demonstrate that adenine nucleotides induce large asymmetric conformational changes in full-length yeast and human MutLα and that these changes are associated with significant increases in secondary structure. These data reveal an ATPase cycle in which sequential nucleotide binding, hydrolysis, and release modulate the conformational states of MutLα.
