Neurogenic locus notch homolog protein 3 negative regulatory region (Notch3 NRR) (Notch3 NRR)

The Notch3 receptor negative regulatory region (NRR) is a critical structural domain of the Notch3 protein that maintains the receptor in an autoinhibited state until ligand-induced activation occurs [1, 2]. It is composed of three Lin-12/Notch repeats (LNR) and a heterodimerization domain (HD) that physically shield the S2 proteolytic cleavage site from ADAM-family metalloproteases [2]. Upon binding to ligands such as Jagged or Delta-like on adjacent cells, mechanical force triggers a conformational change in the NRR, exposing the S2 site and initiating the signaling cascade that leads to the release of the Notch intracellular domain [3]. This domain is a key therapeutic target in oncology, particularly for cancers like ovarian and lung cancer where Notch3 is overexpressed and drives tumor progression [4]. Monoclonal antibodies, such as tarextumab, are designed to bind the NRR and lock it in its closed conformation, effectively blocking receptor activation [5]. Additionally, the Notch3 receptor is vital for vascular smooth muscle cell function, and mutations in the gene are linked to CADASIL, a hereditary stroke disorder [6]. Targeting the NRR specifically allows for more selective inhibition compared to pan-Notch inhibitors like gamma-secretase inhibitors [4]. However, therapeutic use is often limited by gastrointestinal toxicities resulting from the inhibition of Notch signaling in the gut [5].

Other names

Notch3 NRRNotch 3 negative regulatory regionNotch3 LNR-HD domainNeurogenic locus notch homolog protein 3 NRR

Stabilization of the negative regulatory region (NRR) in an autoinhibited conformation to prevent S2 proteolytic cleavage by ADAM metalloproteases, thereby inhibiting the release of the Notch intracellular domain and subsequent downstream signaling [4, 5].