Intramembrane Proteolysis
Activation by Proteolysis

Author: Gianpiero Pescarmona
Date: 24/07/2008


Regulated intramembrane proteolysis (RIP) is a novel signaling paradigm.

RIP requires two proteolytic steps

  • extracytosolic processing of a polytopic membrane protein that appears to be a prerequisite for the second step
  • intramembrane cleavage.

Regulated intramembrane proteolysis: A control mechanism conserved from bacteria to humans 2000

Extracytosolic processing

The extracellular free peptides can function either as nutrients (AA and copper supply) or signals for the surrounding cells. In most cases they are taken up by surrounding cells through endocytosis. This process overlap with cell autophagy.

Intramembrane cleavage.

RIP is realized as a mechanism of signal transduction when the cytosolic fragment the intramembrane cleavage is released into the cytoplasm for subsequent translocation into the nucleus to regulate gene transcription ( transcription factor ).

The list of factors activated in this way includes:

Proteolytic activation

the proteolytic shedding of the ectodomain

Regulation of the intramembrane cleavage of Notch begins at the cell surface where ligand (delta, jagged, serrate) binding to Notch elicits a conformational change that facilitates the proteolytic shedding of the Notch ectodomain by a member of the disintegrin and metalloproteinase (ADAM) family.

the proteolytic shedding of the endodomain (transcriptio factor)


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