proteolyc.pptx
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This paper discusses the proteolytic cleavage of the Notch receptor protein. Notch signaling requires two cleavage events - one mediated by ADAM metalloproteases (HIT) and the other by gamma-secretase (RUN). These cleavages are necessary to release the Notch intracellular domain, which then translocates to the nucleus to regulate transcription of target genes.
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proteolyc.pptx
- 2. van Tetering, G. & Vooijs, M. Proteolytic cleavage of Notch: "HIT and RUN". Curr Mol Med 11, 255–269 (2011).
- 3. van Tetering, G. & Vooijs, M. Proteolytic cleavage of Notch: "HIT and RUN". Curr Mol Med 11, 255–269 (2011).
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- Fig. (1). Overview of Notch proteolysis. A schematic overview of the Notch signaling pathway showing the proteolytic events. During maturation and transport of the receptor to the membrane Notch gets cleaved in the Golgi system at Site-1 (S1) by a furin-like convertase, resulting in a heterodimeric transmembrane receptor. At the cell surface in the absence of ligand the receptor is proteolysis-resistant. Only upon binding of ligand, inducing a substantial conformational change, the metalloprotease ADAM10 is able to cleave Notch at the newly exposed Site-2 (S2). This sheds off the NECD which can be transendocytosed into the ligand-expressing cell. On the receptor-expressing cell S2 cleavage results in a NEXT fragment that either is directly cleaved at the membrane at Val1744 (NICD-V) by the -secretase complex, or NEXT is internalized and processed in endocytic compartments by -secretase at Ser1747 (NICD-S). NICD translocates to the nucleus where it participates in a co-activator complex binding to CSL and starts target gene transcription. An additional cleavage at Site-4 (S4) is mediated by the -secretase in the centre of the transmembrane domain resulting in the N fragment, probably meant to clear residual Notch fragments from the membrane.
- Fig. (2). Partial alignments of the different cleavage regions. Sequences from Notch receptors of fly, worm, rodent and human are shown. Upper panel: The S1 cleavage region shows low conservation. Yet, in every species possible furin sites could be identified. Middle panel: The juxtamembrane region containing the S2 cleavage site shows a high conservation among mammalian receptors that all show Valine residues on the proposed S2 cleavages sites. Lower panel: Transmembrane domains of the various receptors show high conservation, in particular mammalian receptors that all show a Valine residue close to the inner leaflet of the plasma membrane. Yet, also worm and fly Notch show conservation of this Valine. Underlined sequences are previously described cleavage sites.