Gamma secretase

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

The protein complex composed of four subunits, whose presence is sufficient for the function: a presenilin -1 - or -2 homodimer, nicastrin, stabilization factor APH -1 and presenilin enhancer 2 (PEN -2). Since APH- 1 in three isoforms occurs ( APH -1A -Long, APH -1A Short, APH -1B ), six different isoforms of the gamma -secretase are possible. More recent findings, where a fifth protein, CD147, as a nonessential regulator of the activity of the complex is lowered, have now disproved.

Assembly of the complex

During the formation of the gamma -secretase complex, the subunits can be modified to a great extent by limited proteolysis. An essential step for activation of the complex is the autocatalytic cleavage of presenilin in a C-terminal and an N-terminal fragment. The role of the Nicastrins is the stabilization of the complex and the control of the intracellular transport.

PEN -2 connects to the complex by binding to the transmembrane domain of the Präsenilins. It stabilizes the complex after cleavage of the Präsenilins. Other roles of the PEN -2 are still unknown. APH -1 binds a conserved α -helix binding motif to the complex and is involved in the initiation of the formation of the complex by immature components.

The gamma - secretase is formed by proteolysis in the endoplasmic reticulum ( ER). He is then transported to the late ER, where it intersects its substrates. It also occurs in mitochondria, where it is believed to play a supportive role in apoptosis.

Nicastrin

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

APH -1

APH -1 ( anterior pharynx - defective 1) is a protein which was first found in the Notch pathway in Caenorhabditis elegans as regulators of the Nicastrin localization at the cell surface. Later, APH -1 homologues have been in other organisms - so also in man - identified where this part of the gamma - secretase complex are. APH -1 and PEN -2 are regarded as regulators of the maturation of catalytically active Präsenilins.

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

PEN -2

PEN -2 ( presenilin enhancer 2 for short, engl. " Presenilin - 2 amplifier " ) is an integral membrane protein of 101 amino acids. Probably both the N-terminus and the C -terminus are post-translationally in the first lumen of the endoplasmic reticulum and subsequently out of the cell. Both the conserved sequence motif Asp -Tyr- Leu-Ser -Phe is necessary for the formation of the active gamma - secretase at the C -terminus as well as the overall length of the C-terminus.

Gamma secretase

Assembly of the complex

Nicastrin

APH -1

PEN -2

Further Reading