Beta secretase: Difference between revisions

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Alzheimer's disease is a neurodegenerative disease, and one of the most common forms of dementia. Early symptoms include things like loss of short-term memory and impairment of some physical movements. As the disease progresses, memory impairment worsens, muscle deteriorates, and the patient eventually dies. Patients of the later stages of Alzheimer's usually need to be taken care of as they are not able to take care of themselves at that point.

Alzheimer's disease occurs by the ~~build up plaques~~ that lead to the death of neurons. The plaques themselves are formed from the buildup of amyloid beta (Aβ). Aβ is produced by the cleavage of amyloid precursor protein (APP), an integral membrane protein found in the synapses of neurons. The cleavage of APP itself can go down one of two pathways:

Alzheimer's disease occurs by plaques in the walls of vessels and extracellular parenchyma in the brain that lead to the death of neurons. The plaques themselves are formed from the buildup of amyloid beta (Aβ). Aβ is a fragment of about 43 amino acids, and is produced by the cleavage of amyloid precursor protein (APP), an integral membrane protein found in the synapses of neurons. The cleavage of APP itself can go down one of two pathways:

[[Image:APP2.png|center]]

A. In the first pathway, α-secretase cleaves APP somewhere within the Aβ region. This creates a fragment known as sAPPα. This fragment is beneficial to neurons as it helps to protect them.

A. In the first pathway, α-secretase cleaves APP somewhere within the Aβ region. This creates a fragment known as sAPPα. This fragment is beneficial to neurons as it helps to protect them. γ-Secretase can also follow up and cleave at its target, forming a fragment known as p3, whose function is unknown.

B. In the second pathway, β-secretase cleaves APP at the N-terminus of Aβ, creating a fragment of sAPPβ. Then γ-secretase cleaves APP at the C-terminus of Aβ, which exists along the transmembrane domain of APP. At this point, Aβ is released and allowed to accumulate with other fragments, forming plaques.

β-Secretase is able to cleave Aβ at its N-terminus due to the nucleophilic attack that occurs upon the the active site of β-secretase. After the water molecule is coordinated between the carbonyls of the aspartates and the ~~N-terminus~~ of Aβ, the two are able to react, forcing the N-terminus to break its bond with sAPPβ.

β-Secretase is able to cleave Aβ at its N-terminus due to the nucleophilic attack that occurs upon the the active site of β-secretase. This β-site region which β-secretase binds to is made up of methionine-aspartate-alanine (MDA). The aspartates on β-secretase bind to the aspartate of the β-site on APP (Asp672). This reaction only occurs under acidic pH conditions (somewhere between 1.88 and 3.65 so that the Aβ's aspartate will have the protonated R group hydroxyl, but β-secretase's aspartates will have deprotonated carbonyls). After the water molecule is coordinated between the carbonyls of the aspartates and the amine group and R group hydroxyl of the aspartate on Aβ, the two are able to react, forcing the N-terminus to break its bond with sAPPβ.

β-Secretase has a specific binding region, where it only binds to the MDA sequence on APP. Mutations and/or radical insertions in the β-site keeps β-secretase from binding to APP. Additionally, shortening of the 10s loop also causes β-secretase to lose its binding ability. This either comes from Gly11 being too far to bond with the substrate, or just the removal of Gly11 as part of the loop. Without the loop, β-secretase is unable to stabilize its interaction with APP and is unable to cleave it.

==Inhibition of Beta Secretase==

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*Patel S, Vuillard L, Cleasby A, Murray CW, Yon J (2004). "Apo and Inhibitor Complex Structures of BACE (β-secretase)". ''J.Mol.Biol.'' '''343''':407.

*Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, Luo Y, Fisher S, Fuller J, Edenson S, Lile J, Jarosinski MA, Biere AL, Curran E, Burgess T, Louis JC, Collins F, Treanor J, Rogers G, Citron M (1999). "β-Secretase Cleavage of Alzheimer's Amyloid Precursor Protein by the Transmembrane Aspartic Protease BACE". ''Science'' '''286''':735-741.

*Willem M, Dewachter I, Smyth N, Dooren TV, Borghgraef P, Haass C, Leuven FV (2004). "β-Site Amyloid Precursor Protein Cleaving Enzyme 1 Increases Amyloid Deposition in Brain Parenchyma but Reduces Cerebrovascular Amyloid Angiopathy in Aging BACE x APP[V717I] Double-Transgenic Mice". ''The American Journal of Pathology'' '''165''':1621-1631.

*Wilquet V, Strooper BD (2004). "Amyloid-beta Precursor Protein Processing in Neurodegeneration". ''Current Opinion in Neurobiology'' '''14''':582-588.

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@@ Line 19: / Line 19: @@
 Alzheimer's disease is a neurodegenerative disease, and one of the most common forms of dementia. Early symptoms include things like loss of short-term memory and impairment of some physical movements. As the disease progresses, memory impairment worsens, muscle deteriorates, and the patient eventually dies. Patients of the later stages of Alzheimer's usually need to be taken care of as they are not able to take care of themselves at that point.
-Alzheimer's disease occurs by the build up plaques that lead to the death of neurons. The plaques themselves are formed from the buildup of amyloid beta (Aβ). Aβ is produced by the cleavage of amyloid precursor protein (APP), an integral membrane protein found in the synapses of neurons. The cleavage of APP itself can go down one of two pathways:
+Alzheimer's disease occurs by plaques in the walls of vessels and extracellular parenchyma in the brain that lead to the death of neurons. The plaques themselves are formed from the buildup of amyloid beta (Aβ). Aβ is a fragment of about 43 amino acids, and is produced by the cleavage of amyloid precursor protein (APP), an integral membrane protein found in the synapses of neurons. The cleavage of APP itself can go down one of two pathways:
 [[Image:APP2.png|center]]
-A. In the first pathway, α-secretase cleaves APP somewhere within the Aβ region. This creates a fragment known as sAPPα. This fragment is beneficial to neurons as it helps to protect them.
+A. In the first pathway, α-secretase cleaves APP somewhere within the Aβ region. This creates a fragment known as sAPPα. This fragment is beneficial to neurons as it helps to protect them. γ-Secretase can also follow up and cleave at its target, forming a fragment known as p3, whose function is unknown.
 B. In the second pathway, β-secretase cleaves APP at the N-terminus of Aβ, creating a fragment of sAPPβ. Then γ-secretase cleaves APP at the C-terminus of Aβ, which exists along the transmembrane domain of APP. At this point, Aβ is released and allowed to accumulate with other fragments, forming plaques.
-β-Secretase is able to cleave Aβ at its N-terminus due to the nucleophilic attack that occurs upon the the active site of β-secretase. After the water molecule is coordinated between the carbonyls of the aspartates and the N-terminus of Aβ, the two are able to react, forcing the N-terminus to break its bond with sAPPβ.
+β-Secretase is able to cleave Aβ at its N-terminus due to the nucleophilic attack that occurs upon the the active site of β-secretase. This β-site region which β-secretase binds to is made up of methionine-aspartate-alanine (MDA). The aspartates on β-secretase bind to the aspartate of the β-site on APP (Asp672). This reaction only occurs under acidic pH conditions (somewhere between 1.88 and 3.65 so that the Aβ's aspartate will have the protonated R group hydroxyl, but β-secretase's aspartates will have deprotonated carbonyls). After the water molecule is coordinated between the carbonyls of the aspartates and the amine group and R group hydroxyl of the aspartate on Aβ, the two are able to react, forcing the N-terminus to break its bond with sAPPβ.
+β-Secretase has a specific binding region, where it only binds to the MDA sequence on APP. Mutations and/or radical insertions in the β-site keeps β-secretase from binding to APP. Additionally, shortening of the 10s loop also causes β-secretase to lose its binding ability. This either comes from Gly11 being too far to bond with the substrate, or just the removal of Gly11 as part of the loop. Without the loop, β-secretase is unable to stabilize its interaction with APP and is unable to cleave it.
 ==Inhibition of Beta Secretase==
@@ Line 47: / Line 49: @@
 *Patel S, Vuillard L, Cleasby A, Murray CW, Yon J (2004). "Apo and Inhibitor Complex Structures of BACE (β-secretase)". ''J.Mol.Biol.'' '''343''':407.
 *Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, Luo Y, Fisher S, Fuller J, Edenson S, Lile J, Jarosinski MA, Biere AL, Curran E, Burgess T, Louis JC, Collins F, Treanor J, Rogers G, Citron M (1999). "β-Secretase Cleavage of Alzheimer's Amyloid Precursor Protein by the Transmembrane Aspartic Protease BACE". ''Science'' '''286''':735-741.
+*Willem M, Dewachter I, Smyth N, Dooren TV, Borghgraef P, Haass C, Leuven FV (2004). "β-Site Amyloid Precursor Protein Cleaving Enzyme 1 Increases Amyloid Deposition in Brain Parenchyma but Reduces Cerebrovascular Amyloid Angiopathy in Aging BACE x APP[V717I] Double-Transgenic Mice". ''The American Journal of Pathology'' '''165''':1621-1631.
+*Wilquet V, Strooper BD (2004). "Amyloid-beta Precursor Protein Processing in Neurodegeneration". ''Current Opinion in Neurobiology'' '''14''':582-588.