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Gamma secretase activating protein (GSAP) present in β-amyloid pathway orchestrates the formation of β-amyloid plaques by γ-secretase activation and is an emerging therapeutic target for the treatment of Alzheimer's disease. It forms a ternary complex with γ secretase and APP C-99. However, there are limited reports for the interaction of APP C-99 with GSAP. Here, we report the characterization of purified maltose binding protein tagged human GSAP and its interaction with synthetic APP C-99 peptide fragments (712IATVIVITLVMLKKQ727 (712IQ727), 719TLVMLKKKQYTSIHHGVVEVDAAVT743 (719TT743) 734GVVEVDAAVTPEERHLSKMQQNGY757 (734GY757), and 746ERHLSKMQQNGYENPTYKFFEQMQN770 (746EN770)). The results emphasize the selective interaction of peptide (719TT743) with MBP-GSAP with a dissociation constant of 0.136 µM. Further, computational modeling of the GSAP - 719TT743 complex finds an optimal bound pose of 719TT743 within an extended groove on the surface of GSAP. The preliminary results highlight the interaction between the two major proteins in the plausible ternary complex; APP C-99-GSAP- γ secretase. It paves a futuristic path to investigate the GSAP- APP C-99 binding in detail and accentuate the role of GSAP in the β-amyloid pathway.
This article was published in the following journal.
Name: ACS chemical neuroscience
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A precursor to the AMYLOID BETA-PROTEIN (beta/A4). Alterations in the expression of the amyloid beta-protein precursor (ABPP) gene, located on chromosome 21, plays a role in the development of the neuropathology common to both ALZHEIMER DISEASE and DOWN SYNDROME. ABPP is associated with the extensive extracellular matrix secreted by neuronal cells. Upon cleavage, this precursor produces three proteins of varying amino acid lengths: 695, 751, and 770. The beta/A4 (695 amino acids) or beta-amyloid protein is the principal component of the extracellular amyloid in senile plaques found in ALZHEIMER DISEASE; DOWN SYNDROME and, to a limited extent, in normal aging.
Peptides generated from AMYLOID BETA-PEPTIDES PRECURSOR. An amyloid fibrillar form of these peptides is the major component of amyloid plaques found in individuals with Alzheimer's disease and in aged individuals with trisomy 21 (DOWN SYNDROME). The peptide is found predominantly in the nervous system, but there have been reports of its presence in non-neural tissue.
A 4-kDa protein, 39-43 amino acids long, expressed by a gene located on chromosome 21. It is the major protein subunit of the vascular and plaque amyloid filaments in individuals with Alzheimer's disease and in aged individuals with trisomy 21 (DOWN SYNDROME). The protein is found predominantly in the nervous system, but there have been reports of its presence in non-neural tissue.
A heterogeneous group of sporadic or familial disorders characterized by AMYLOID deposits in the walls of small and medium sized blood vessels of CEREBRAL CORTEX and MENINGES. Clinical features include multiple, small lobar CEREBRAL HEMORRHAGE; cerebral ischemia (BRAIN ISCHEMIA); and CEREBRAL INFARCTION. Cerebral amyloid angiopathy is unrelated to generalized AMYLOIDOSIS. Amyloidogenic peptides in this condition are nearly always the same ones found in ALZHEIMER DISEASE. (from Kumar: Robbins and Cotran: Pathologic Basis of Disease, 7th ed., 2005)
A type of extracellularly deposited substance composed of an amyloid protein and additional components including HEPARAN SULFATE PROTEOGLYCAN; LAMININ; COLLAGEN TYPE IV; SERUM AMYLOID P-COMPONENT; and APOLIPOPROTEINS E which together form characteristic amyloid fibrils. The core of amyloid fibrils is formed by the stacking of overlapping beta-pleated sheet domains of the amyloid protein. There are many different amyloid proteins that have been found forming the core of the fibrils in vivo. However, amyloid can be formed from any protein that exposes beta-pleated strand conformations during unfolding or refolding. A common characteristic of amyloid is the ability to bind such dyes as CONGO RED and thioflavine.
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Neurology - Central Nervous System (CNS)
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