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Notch1 Heterodimerization Domain in T-cell Acute Lymphoblastic Leukaemia

Notch1 Heterodimerization Domain. Juxtamembrane peptide containing the S2 site in green, negative regulatory domain in blue.

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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.

1 Structure and Function of Notch1
- 1.1 Proteolytic Events During Notch1 Secretion and Signal Transduction
  - 1.1.1 Furin-type Convertase Cleavage
  - 1.1.2 Additional Cleavages in Response to Receptor Activation
- 1.2 Heterodimerization Domain and Negative Regulatory Region
2 T-cell Acute Lymphoblastic Leukaemia
3 Relevance
4 Structural highlights

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

Relevance

Structural highlights

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You may include any references to papers as in: the use of JSmol in Proteopedia ^[3] or to the article describing Jmol ^[4] to the rescue.

References

↑ Aster JC, Pear WS, Blacklow SC. Notch signaling in leukemia. Annu Rev Pathol. 2008;3:587-613. doi:, 10.1146/annurev.pathmechdis.3.121806.154300. PMID:18039126 doi:http://dx.doi.org/10.1146/annurev.pathmechdis.3.121806.154300
↑ ^2.0 ^2.1 Gordon WR, Vardar-Ulu D, L'Heureux S, Ashworth T, Malecki MJ, Sanchez-Irizarry C, McArthur DG, Histen G, Mitchell JL, Aster JC, Blacklow SC. Effects of S1 cleavage on the structure, surface export, and signaling activity of human Notch1 and Notch2. PLoS One. 2009 Aug 24;4(8):e6613. PMID:19701457 doi:10.1371/journal.pone.0006613
↑ Hanson, R. M., Prilusky, J., Renjian, Z., Nakane, T. and Sussman, J. L. (2013), JSmol and the Next-Generation Web-Based Representation of 3D Molecular Structure as Applied to Proteopedia. Isr. J. Chem., 53:207-216. doi:http://dx.doi.org/10.1002/ijch.201300024
↑ Herraez A. Biomolecules in the computer: Jmol to the rescue. Biochem Mol Biol Educ. 2006 Jul;34(4):255-61. doi: 10.1002/bmb.2006.494034042644. PMID:21638687 doi:10.1002/bmb.2006.494034042644

Proteopedia Page Contributors and Editors (what is this?)

Apolena Zounarová

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 === 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 <ref name="gordon">DOI 10.1371/JOURNAL.PONE.0006613</ref>. 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 <ref name="gordon" /><ref="uniprot">DOI 10.1093/NAR/GKAA1100</ref>.
 ====Additional Cleavages in Response to Receptor Activation====