Structural Basis for Cooperative Transcription Factor Binding to the CBP Coactivator

Abstract

Transcription, copying the code of DNA into RNA, can be regulated by many proteins, with CREB‐Binding Protein (CBP), being a very common co‐activator. The Mt. Empire SMART Team (Students Modeling A Research Topic) modeled a particular section of this protein called KIX using 3D printing technology. Although the KIX region is relatively small, it can bind to two proteins at the same time. Two such proteins are the activation domains of the DNA‐binding proteins, MLL and c‐Myb. When KIX binds to MLL, the binding causes a slight change in a segment of KIX. The conformational change in KIX due to MLL helps c‐Myb to bind to KIX. A similar process happens in reverse, with KIX and c‐Myb binding allowing MLL to bind more effectively. We have constructed a model, based upon an NMR structure, which explores the close proximity of the residues for this cooperative interaction and also highlights the structural changes specific to KIX. Although KIX undergoes a slight structural change, the activation domains experience a massive change in structure, from disordered to helical. MLL and c‐Myb bind to DNA at target regions as well as KIX, which recruits CBP with the machinery to their target genes to relax the DNA structure and prepare for transcription. Many of the proteins that KIX and CBP bind to have been shown to be oncogenic, as well as important in memory formation and embryonic development. Supported by a grant from the HHMI Pre‐College Program.