Ectodomain shedding

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The process of ectodomain shedding , which is also described as splitting off the ectodomain , is the proteolytic separation of the extracellular domains ( ectodomains ) of many membrane proteins .

description

Schematic representation of the ectodomain shedding with an ADAM metalloprotease.

During ectodomain shedding, a number of membrane proteins, such as growth factors , cytokines , receptors or cell adhesion molecules (CAMs), are split by certain metalloproteases - these enzymes are also called sheddases . These sheddases include the ADAMs ( A Disintegrin And Metalloprotease ) ADAM9 , ADAM10 and ADAM17 from metazincin-Family. The splitting off of the membrane proteins results in considerable changes on the surface of the cells, which can have a major impact on communication between the cell and therapeutic measures, for example. In addition, during ectodomain shedding, free, dissolved regulator proteins are created in the extracellular space .

Ectodomain shedding is involved in a number of pathophysiological processes such as inflammation , cell degeneration , apoptosis and the development of cancer ( oncogenesis ).

Schematic representation of the cleavage of the APP by α-, β- and γ-secretases
Scheme of the competing processes between α- and β-secretase (s)

Even in the case of Alzheimer's disease , the ectodomain shedding plays an important role. The α-secretases , for example ADAM 9, ADAM 10 and ADAM 17, cut the integral membrane protein APP ( amyloid precursor protein ) at the “right” point (near the cell membrane), while the β-secretase (BACE1) cut the APP cuts at the "wrong" point (further in the extracellular space). The γ-secretase then cuts - regardless of whether the α- or β-secretase has previously cut the APP - the APP residue within the cell membrane. The larger segment (38, 40 or 42 amino acids ), called Aβ, which is produced in the case of the first cut  , leads to the amyloid plaques , while the fragment produced in the case of α-secretase, called P3, does not form any plaques.

The antigen-shedding is a special form of ectodomain-shedding.

Individual evidence

  1. ^ J. Schlöndorff and CP Blobel: Metalloprotease-disintegrins: modular proteins capable of promoting cell-cell interactions and triggering signals by protein-ectodomain shedding. In: J Cell Sci 112, 1999, pp. 3603-3617, PMID 10523497 (review).
  2. ^ LC Bridges and RD Bowditch: ADAM-Integrin Interactions: potential integrin regulated ectodomain shedding activity. In: Curr Pharm Des 11, 2005, pp. 837-847. PMID 15777238 (Review)
  3. ↑ J. Mullberg et al: The importance of shedding of membrane proteins for cytokine biology. In: Eur Cytokine Netw 11, 2000, pp. 27-38, PMID 10705296 (review).
  4. ^ CP Blobel: Remarkable roles of proteolysis on and beyond the cell surface. In: Curr Opin Cell Biol 12, 2000, pp. 606-612. PMID 10978897 (Review)
  5. ↑ J. Sy: The disintegrin and metalloproteinase family "ADAM" in the human hematopoietic system. Dissertation, Eberhard-Karls-Universität zu Tübingen, 2002.
  6. ↑ P. Dello Sbarba and E. Rovida: Transmodulation of cell surface regulatory molecules via ectodomain shedding. In: Biol Chem 383, 2002, pp. 69-83, PMID 11928824 (review).
  7. ↑ SF Lichtenthaler: Ectodomain shedding of the amyloid precursor protein: cellular control mechanisms and novel modifiers. In: Neurodegener Dis 3, 2006, pp. 262-269. PMID 17047366 (Review).
  8. ↑ Gregor Larbig: Studies to identify & optimize potential active ingredients for the treatment of Alzheimer's disease. Dissertation, TU Darmstadt, 2007.
  9. ^ Y. Zhang and I. Pastan: High Shed Antigen Levels within Tumors: An Additional Barrier to Immunoconjugate Therapy. In: Clin Cancer Res 14, 2008, pp. 7981-7986, PMID 19088013 (review).

literature