NOTCH1 is a member of NOTCH family receptor proteins which consists of four members (NOTCH1-4). NOTCH proteins are evolutionarily highly conserved signalling proteins responsible for direct transduction of developmental signals at the cell surface into change in a transcriptional profile in the nucleus.
Structure and Function of Notch1
NOTCH receptors are class I transmembrane glycoproteins composed of an extracellular subunit and transmembrane and intracellular subunit, which interact via a specialised heterodimerization domain (HD). The extracellular subunit engages ligand via several EGF-like repeats and further contains three LIN-12/NOTCH repeats (LNR) which stabilise the dimerization domain by holding the two NOTCH subunits together. The transmembrane-intracellular subunit contains a short extracellular juxtamembrane peptide, transmembrane sequence and cytoplasmic domains including RAM domain, nuclear localization signals (NLS), a series of ankyrin repeats, glutamine-rich region (OPA) and C-terminal PEST domain which serves as a ligand-activated transcription factor [1].
Proteolytic Events During Notch1 Secretion and Signal Transduction
Furin-type Convertase Cleavage
Notch1 is posttranslationally modified by a proteolytic cleavage at S1 sites and reaches the plasma membrane as a heterodimer. Non-cleaved Notch1 is autoinhibited. Furin-type convertase is responsible for this process and cleaves Notch1 in at least two places: after R1633 and after R1664 [2]. Both residues are located in a loop exposed into the cytosol and lie approximately 100 and 70 amino acids external from the transmembrane region, respectively [2]<ref="uniprot">DOI 10.1093/NAR/GKAA1100</ref>.
Additional Cleavages in Response to Receptor Activation
Heterodimerization Domain and Negative Regulatory Region
T-cell Acute Lymphoblastic Leukaemia
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Structural highlights
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