The CDY (chromodomain on the Y) proteins play an essential role in normal spermatogenesis and brain development. Dysregulation of their expression has been linked to male infertility and various neurological diseases. Like the chromodomains of HP1 and Polycomb, the CDY chromodomains also recognize the lysine-methylated ARKS motif embedded in histone and non-histone proteins. Interestingly, the CDY chromodomains exhibit different binding preferences for the lysine-methylated ARKS motif in different sequence contexts. Here, we present the structural basis for selective binding of CDY1 to H3K9me3 and preferential binding of CDYL2 to H3tK27me3 over H3K27me3. In addition, we use a CDYL1/2-selective compound, UNC4850, to gain further insight into the molecular mechanisms underlying CDYL2 binding specificity. Our work also provides critical implications that CDYL1b's role in the regulation of neural development is dependent on its recognition of the lysine-methylated ARKS motif.

CDY（Y上的色域）蛋白在正常的精子发生和大脑发育中起着至关重要的作用。其表达失调与男性不育和各种神经系统疾病有关。像HP1和Polycomb的色域一样，CDY色域也可以识别组蛋白和非组蛋白中嵌入的赖氨酸甲基化的ARKS基序。有趣的是，在不同的序列背景下，CDY染色体结构域对赖氨酸甲基化的ARKS基序表现出不同的结合偏好。在这里，我们介绍了CDY1选择性结合H3K9me3和CDYL2优先结合H3tK27me3的结构基础。此外，我们使用CDYL1 / 2选择性化合物UNC4850，以进一步了解CDYL2结合特异性的分子机制。