Structural Superimposition

Abstact

DNA methyltransferase DNMT3A is a key enzyme responsible for establishing DNA methylation patterns during mammalian development. T-cell leukemia/lymphoma 1 A (TCL1A) is a proto-oncogene expressed mainly in embryonic and fetal tissues, as well as in specific lymphocyte populations. In this study, we determined the structure of the murine DNMT3A-TCL1A complex using single-particle cryo-electron microscopy. The complex adopts a linear conformation, with two TCL1A dimers bound to the catalytic domain of DNMT3A to form a heterohexamer. TCL1A competitively binds to the same structural interface on DNMT3A as DNMT3L, but produces an inhibitory-rather than an activating-effect on the catalytic activity of DNMT3A. Furthermore, comparative analysis with previously reported assembly modes of murine TCL1A revealed that the TCL1A dimer complex we resolved adopts distinct molecular conformations and interaction mechanisms. Our findings elucidate the allosteric mechanism by which murine TCL1A inhibits DNMT3A activity, providing a structural basis for understanding mammalian epigenetic reprogramming.