TY - JOUR T1 - Structural basis for the binding selectivity of human CDY chromodomains JF - bioRxiv DO - 10.1101/820647 SP - 820647 AU - Cheng Dong AU - Yanli Liu AU - Tian-Jie Lyu AU - Serap Beldar AU - Kelsey N. Lamb AU - Wolfram Tempel AU - Yanjun Li AU - Zoey Li AU - Lindsey I. James AU - Su Qin AU - Yun Wang AU - Jinrong Min Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/11/07/820647.abstract N2 - The CDY (Chromodomain on the Y) family is a small family of chromodomain containing proteins, whose chromodomains closely resemble those in HP1 and Polycomb. The CDY 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. Based on our structural, binding and mutagenesis data, we synthesized a more CDYL1/2 selective peptidic ligand UNC4850. Our work provides critical implications that CDYL1b’s role in the regulation of neural development is dependent on its recognition of lysine-methylated ARKS motifs. ER -