Structurally conserved binding motifs of transcriptional regulators to notch nuclear effector CSL

Abstract

This mini review discusses the protein complexes comprised of the universal Notch signaling transcription factor, CSL (CBF1/Su(H)/Lag-1), and its activating or repressing transcriptional coregulation partners. Many of these complex structures have been solved crystallographically as well as undergoing extensive binding studies with wild-type and mutant variants. Notch signaling is critically important in a large variety of basic biological processes: cell proliferation, differentiation, cell cycle control to name a few. Aberrant Notch thus remains a coveted target for pharmaceutical intervention. To that end, we provide a molecular-level summary of the similarities and differences in the Notch coregulator complexes that ultimately govern these processes. We highlight a conserved binding motif that multiple superficially unrelated proteins have adopted to become involved in Notch target gene regulation. As CSL-interacting small molecules begin to be characterized, this review will provide insight to potential binding sites and differential complex disruption.

Impact statement

Proper Notch signaling regulation is informed by many distinct protein complexes involving a single nuclear effector. A decade of research into these protein complexes yields multiple crystal structures and a wealth of binding data to guide drug development for Notch-related diseases – cancer, cardiovascular, development disorders.