Notch intracellular domain ankyrin repeat domain (NICD ANK) (NICD ANK)

The Notch intracellular domain ankyrin repeat domain (NICD ANK) is a pivotal structural motif within the Notch signaling pathway, composed of seven tandem ankyrin repeats that mediate essential protein-protein interactions [1]. Following the proteolytic cleavage of the Notch receptor, the NICD translocates to the nucleus where the ANK domain acts as a scaffold to recruit the DNA-binding protein CSL and the co-activator Mastermind-like (MAML) [2]. This assembly forms a ternary transcription complex that activates target genes such as HES1 and MYC, which are critical for cell proliferation and differentiation [3]. Aberrant activation of the Notch pathway, frequently involving the ANK domain's recruitment capabilities, is implicated in various cancers, including T-cell acute lymphoblastic leukemia and breast cancer [4]. Because the ANK domain is indispensable for transcriptional activation, it has become a high-priority target for small molecules and stapled peptides designed to disrupt the Notch transcription complex [5]. However, therapeutic intervention is complicated by the potential for "on-target" toxicities, such as gastrointestinal distress, due to the pathway's role in maintaining intestinal stem cell niches [6].

Other names

Notch ANK domainAnkyrin repeat domain of NotchNICD ankyrin repeatsNotch intracellular domain

Inhibition of the Notch ternary transcription complex by disrupting protein-protein interactions mediated by the ankyrin repeat domain [5, 6].