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首页> 外文期刊>Journal of Molecular Biology >Molecular mechanism of MLL PHD3 and RNA recognition by the Cyp33 RRM domain.
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Molecular mechanism of MLL PHD3 and RNA recognition by the Cyp33 RRM domain.

机译：Cyp33 RRM结构域对MLL PHD3和RNA识别的分子机制。

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摘要

The nuclear protein cyclophilin 33 (Cyp33) is a peptidyl-prolyl cis-trans isomerase that catalyzes cis-trans isomerization of the peptide bond preceding a proline and promotes folding and conformational changes in folded and unfolded proteins. The N-terminal RNA-recognition motif (RRM) domain of Cyp33 has been found to associate with the third plant homeodomain (PHD3) finger of the mixed lineage leukemia (MLL) proto-oncoprotein and a poly(A) RNA sequence. Here, we report a 1.9 A resolution crystal structure of the RRM domain of Cyp33 and describe the molecular mechanism of PHD3 and RNA recognition. The Cyp33 RRM domain folds into a five-stranded antiparallel beta-sheet and two alpha-helices. The RRM domain, but not the catalytic module of Cyp33, binds strongly to PHD3, exhibiting a 2 muM affinity as measured by isothermal titration calorimetry. NMR chemical shift perturbation (CSP) analysis and dynamics data reveal that the beta strands and the beta2-beta3 loop of the RRM domain are involved in the interaction with PHD3. Mutations in the PHD3-binding site or deletions in the beta2-beta3 loop lead to a significantly reduced affinity or abrogation of the interaction. The RNA-binding pocket of the Cyp33 RRM domain, mapped on the basis of NMR CSP and mutagenesis, partially overlaps with the PHD3-binding site, and RNA association is abolished in the presence of MLL PHD3. Full-length Cyp33 acts as a negative regulator of MLL-induced transcription and reduces the expression levels of MLL target genes MEIS1 and HOXA9. Together, these in vitro and in vivo data provide insight into the multiple functions of Cyp33 RRM and suggest a Cyp33-dependent mechanism for regulating the transcriptional activity of MLL.
机译：核蛋白亲环蛋白33（Cyp33）是一种肽基-脯氨酰顺反异构酶，可催化脯氨酸之前的肽键的顺反异构化，并促进折叠和未折叠蛋白质的折叠和构象变化。已发现Cyp33的N端RNA识别基序（RRM）域与混合谱系白血病（MLL）原癌蛋白和poly（A）RNA序列的第三个植物同源域（PHD3）手指相关。在这里，我们报告Cyp33的RRM域的1.9 A分辨率晶体结构，并描述了PHD3和RNA识别的分子机制。 Cyp33 RRM结构域折叠成一个五链的反平行β-折叠和两个α-螺旋。 RRM结构域，但不是Cyp33的催化模块，与PHD3牢固结合，显示2μM的亲和力（通过等温滴定热分析法测定）。 NMR化学位移扰动（CSP）分析和动力学数据表明，RRM域的β链和β2-β3环参与了与PHD3的相互作用。 PHD3结合位点的突变或beta2-beta3环中的删除会导致相互作用的亲和力或废止率大大降低。 Cyp33 RRM结构域的RNA结合口袋（基于NMR CSP和诱变定位）与PHD3结合位点部分重叠，并且在存在MLL PHD3的情况下废除了RNA缔合。全长Cyp33充当MLL诱导的转录的负调节剂，并降低MLL目标基因MEIS1和HOXA9的表达水平。这些体外和体内数据共同提供了Cyp33 RRM多种功能的见解，并提出了Cyp33依赖性机制来调节MLL的转录活性。

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