TY - JOUR T1 - Sibling rivalry among the ZBTB transcription factor family: homodimers versus heterodimers JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.202201474 VL - 5 IS - 11 SP - e202201474 AU - Sofia Piepoli AU - Sarah Barakat AU - Liyne Nogay AU - Büşra Şimşek AU - Umit Akkose AU - Hakan Taskiran AU - Nazife Tolay AU - Melike Gezen AU - Canberk Yarkın Yeşilada AU - Mustafa Tuncay AU - Ogün Adebali AU - Canan Atilgan AU - Batu Erman Y1 - 2022/11/01 UR - https://www.life-science-alliance.org/content/5/11/e202201474.abstract N2 - The BTB domain is an oligomerization domain found in over 300 proteins encoded in the human genome. In the family of BTB domain and zinc finger–containing (ZBTB) transcription factors, 49 members share the same protein architecture. The N-terminal BTB domain is structurally conserved among the family members and serves as the dimerization site, whereas the C-terminal zinc finger motifs mediate DNA binding. The available BTB domain structures from this family reveal a natural inclination for homodimerization. In this study, we investigated the potential for heterodimer formation in the cellular environment. We selected five BTB homodimers and four heterodimer structures. We performed cell-based binding assays with fluorescent protein–BTB domain fusions to assess dimer formation. We tested the binding of several BTB pairs, and we were able to confirm the heterodimeric physical interaction between the BTB domains of PATZ1 and PATZ2, previously reported only in an interactome mapping experiment. We also found this pair to be co-expressed in several immune system cell types. Finally, we used the available structures of BTB domain dimers and newly constructed models in extended molecular dynamics simulations (500 ns) to understand the energetic determinants of homo- and heterodimer formation. We conclude that heterodimer formation, although frequently described as less preferred than homodimers, is a possible mechanism to increase the combinatorial specificity of this transcription factor family. ER -