Proteins secretase

Key Words amyloid /3-protein, secretases, protease inhibitors, immunization, monoclonal antibodies... 

Alzheimer s disease in which the pathogenicity of amyloid peptides depends on proteases, namely secretases, involved in amyloid precursor protein (APP) maturation. This chapter will describe how the proteolysis of chemokines might participate in the neuropathogenesis of HIV infection, thus contributing to the development of the central nervous system disorder termed HIV-associated dementia (HAD). 

Figure 18.5 Schematic representation of possible cleavage sites of APP by a, and y-secretase and the production of j5-amyloid protein. (I) This shows the disposition of APP molecules in 695, 751 and 770 amino-acid chain lengths. Much of it is extracellular. The /1-amyloid (A/I4) sequence is partly extracellular and partly in the membrane. (II) An enlargement of the /1-amyloid sequence. (Ill) Normal cleavage of APP by a-secretase occurs in the centre of A/I4 sequence to release the extracellular APP while the remaining membrane and intracellular chain is broken down by y-secretase to give two short proteins that are quickly broken down. (IV) In Alzheimer s disease ji rather than a-secretase activity splits off the extracellular APP to leave the full AP4 sequence remaining attached to the residual membrane and intracellular chain. 42/43 amino acid )S-amyloid sequence is then split off by y-secretase activity...

BACE-1 (p-secretase) is one of the enzymes involved in breaking down APP to produce Ap (amyloid p-peptide, Ap40>42), the protein that eventually oligomerizes to form Ap plaques, the hallmark of Alzheimer s disease (AD). Thus an agent that... 

The sustained attractiveness of photolabeling is apparent from its prominence in studies of y-secretase, an intramembrane protease that contributes to forming amyloid-p peptides and is a major target in Alzheimer s disease [60-62]. y-Secretase is a complex of at least four different polypeptides, and is difficult to engage with high-resolution structural methods. However, in a case of this kind that involves a known target, immunodetection of proteins can often specify the target of y-secretase inhibitor photoaffinity probes such as 19, and proteomic mass spectrometry is not needed. 

DTBP also has been used to investigate the dimerization and actin bundling properties of vil-lin (George et al., 2007), the interaction of the Mrell complex with RPA (Olson et al., 2007), the study of gamma-secretase complex assembly (Spasic et al., 2007), and the multi-protein assembly of Kv4.2, KChIP3 and DPP10 (Jerng et al., 2005). 

The functions of these protein and their interactions with each other in the complex and in y-secretase activity are not yet fully defined. PS1 may act as an aspartyl protease itself function as a cofactor critical for the activity of... 

Vassar, R., Bennett, B. D., Babu-Khan, S. et al. P-secretase cleavage of Alzheimer s amyloid precusor protein by the transmembrane aspartic protease BACE. Science 286 735-741, 1999. 

Li, T., Ma, G., Cai, H. etal. Nicastrin is required for assembly of presenilin/gamma-secretase complexes to mediate notch signaling and for processing and trafficking of beta-amyloid precursor protein in mammals. /. Neurosci. 23 3272-3277, 2003. 

Farzan, M., Schnitzler, C. E., Vasilieva, N. et al. BACE2, a P-secretase homolog, cleaves at the (3 site and within the amyloid-P region of the amyloid-P precursor protein. Proc. Natl Acad. Sci. USA 97 9712-9717, 2000. 

Figure 17.5. The precursor molecule APP and the three different proteases a, (i, y secretase that are involved in the processing of APPto fS-amyloid peptide. The aberrant processing of the amyloid precursor protein (APP) leads to accumulation of beta-amyloid fragments, first as protofibrils and then as fibers that aggregate in the senile plaque structures. (See color insert.)...

Involvement of several proteolytic enzymes, secretases, is probably crucial for this process but other hypotheses, including, for example, cholinergic transmission or accumulation of metal ions, have also been considered. Future perspectives in this area concern the search for novel pharmaceuticals that cross the blood-brain barrier, without side effects (e.g., the dyskinesias of L-Dopa), or potent and selective inhibitors of improper cleavage of amyloid protein, or even stem cell therapy to restore neuronal cells. 

Vassar, R., Bennett, B. D., Babu-Khan, S., Kahn, S., Mendiaz, E. A., Denis, P., Teplow, D. B., Ross, S., Amarante, P., Loeloff, R., Luo, Y., Fisher, S., et al. (1999). Beta-secretase cleavage of Alzheimer s amyloid precursor protein by the transmembrane aspartic protease BAGE. Science 286, 735—741. 

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