Gamma secretase

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Scheme drawing of the γ-secretase complex in the cell membrane. The number of transmembrane domains results from the amino acid sequence.

The gamma-secretase is an existing multi-subunit protein complex , and an integral (in the lipid layer of the cell membrane intercalated) membrane protein . The protease subunit of the complex cuts transmembrane proteins within the transmembrane domain . The best-known substrate for gamma secretase is the amyloid precursor protein (APP), a large integral membrane protein. The gamma secretase also processes the protein Notch .

The protein complex consists of four subunits, the presence of which is sufficient for its function: a presenilin -1 or -2 homodimer, nicastrin , stabilization factor APH-1 and presenilin enhancer 2 (PEN-2). Since APH-1 occurs in three isoforms (APH-1A-Long, APH-1A-Short, APH-1B), six different isoforms of gamma-secretase are possible. More recent results, according to which a fifth protein, CD147 , as a non-essential regulator, reduced the activity of the complex, have since been refuted.

Assembling the complex

During the formation of the gamma-secretase complex, the subunits are modified to a large extent by limited proteolysis. An essential step to activate the complex is the autocatalytic cleavage of presenilin into a C-terminal and an N-terminal fragment. The role of nicastrin is to stabilize the complex and control its intracellular transport.

PEN-2 binds to the complex by attaching to the transmembrane domain of presenilin. It stabilizes the complex after the presenilin is split. Further roles of the PEN-2 are still unknown. APH-1 binds to the complex through a conserved α-helix binding motif and is involved in initiating the formation of the complex by components that are still immature.

The gamma secretase complex is formed by proteolysis in the endoplasmic reticulum (ER). It is then transported to the late ER where it cuts its substrates. It is also found in mitochondria , where it is believed to play a supporting role in apoptosis .

Nicastrin

Nicastrin (abbreviation NCT) is required for the maturation and transport of the other proteins in the complex, but is not itself catalytically active.

APH-1

APH-1 ( anterior pharynx-defective 1 ) is a protein that was first found in the Notch pathway in Caenorhabditis elegans as a regulator of the localization of nicastrin on the cell surface. APH-1 homologs were later identified in other organisms - including humans - where they are part of the gamma-secretase complex. APH-1 and PEN-2 are considered to be regulators of the maturation process of the catalytically active presenilin.

APH-1 contains the conserved α-helix binding motif glycine -XXX-glycine (GXXXG for short). This is crucial both in the formation and in the maturation of the gamma-secretase complex.

PEN-2

PEN-2 (short for presenilin enhancer 2 , English "presenilin enhancer 2") is an integral membrane protein made up of 101 amino acids. After translation , both the N-terminus and the C-terminus are probably located first in the lumen of the endoplasmic reticulum and later outside the cell. Both the conserved sequence motif Asp - Tyr - Leu - Ser - Phe at the C-terminus and the total length of the C-terminus are necessary for the formation of the active gamma-secretase complex.

further reading

  • Kimberly WT, LaVoie MJ, Ostaszewski BL, Ye W, Wolfe MS, Selkoe DJ: Gamma-secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2 . In: Proc. Natl. Acad. Sci. USA . 100, No. 11, May 2003, pp. 6382-7. doi : 10.1073 / pnas.1037392100 . PMID 12740439 . PMC 164455 (free full text).
  • Fraering PC, Ye W, Strub JM, et al. : Purification and characterization of the human gamma-secretase complex . In: Biochemistry . 43, No. 30, August 2004, pp. 9774-89. doi : 10.1021 / bi0494976 . PMID 15274632 .
  • Culvenor JG, Ilaya NT, Ryan MT, et al. : Characterization of presenilin complexes from mouse and human brain using Blue Native gel electrophoresis reveals high expression in embryonic brain and minimal change in complex mobility with pathogenic presenilin mutations . In: Eur. J. Biochem. . 271, No. 2, January 2004, pp. 375-85. PMID 14717705 .

Individual evidence

  1. ↑ Lazarov VK, Fraering PC, Ye W, Wolfe MS, Selkoe DJ, Li H: Electron microscopic structure of purified, active gamma-secretase reveals an aqueous intramembrane chamber and two pores . In: Proc. Natl. Acad. Sci. USA . 103, No. 18, May 2006, pp. 6889-94. doi : 10.1073 / pnas.0602321103 . PMID 16636269 . PMC 1458989 (free full text).
  2. ↑ Sato T, Diehl TS, Narayanan S, et al. : Active gamma-secretase complexes contain only one of each component . In: J. Biol. Chem. . 282, No. 47, November 2007, pp. 33985-93. doi : 10.1074 / jbc.M705248200 . PMID 17911105 .
  3. ↑ Shirotani K, Edbauer D, Prokop S, Haass C, Steiner H: Identification of distinct gamma-secretase complexes with different APH-1 variants . In: J. Biol. Chem. . 279, No. 40, October 2004, pp. 41340-5. doi : 10.1074 / jbc.M405768200 . PMID 15286082 .
  4. ↑ Vetrivel KS, Zhang X, X Meckler, et al. : Evidence that CD147 modulation of beta-amyloid (Abeta) levels is mediated by extracellular degradation of secreted Abeta . In: J. Biol. Chem. . 283, No. 28, July 2008, pp. 19489-98. doi : 10.1074 / jbc.M801037200 . PMID 18456655 . PMC 2443668 (free full text).
  5. ↑ C. Kaether, C. Haass, H. Steiner: Assembly, trafficking and function of gamma-secretase . In: Neuro-degenerative diseases . Vol. 3, No. 4-5, 2006, ISSN  1660-2854 pp. 275-283