Beta secretase
From Proteopedia
| 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 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 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: |
| + | |||
| + | [[Image:APP.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. | ||
| + | |||
| + | 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. | ||
==Inhibition of Beta Secretase== | ==Inhibition of Beta Secretase== | ||
==References== | ==References== | ||
Revision as of 09:15, 30 November 2010
|
, also known as BACE (β-site of Amyloid precursor protein Cleaving Enzyme) and Memapsin 2, is an aspartyl protease found in humans. β-Secretase plays an important role in the development of Alzheimer's disease. This has made β-secretase a therapeutic target for pharmacological intervention.
Contents |
Structure of Beta Secretase
β-Secretase is a transmembrane protein, with its active site existing in the extracellular domain of the protein. Due to its nature as an aspartyl protease, β-secretase's active site is made up of . The R groups of both aspartates coordinate a single water molecule between the two of them, allowing for a nucleophilic attack to occur on the carbonyls.
There are two other important features to β-secretase. One is the . The flap is made up of residues 67 through 77. While the active site remains inactive, the flap stays in its open conformation. However, the flap is stabilized while closed over its substrate or some other inhibitor.
The other important feature is the . The 10s loop is located in the S3 pocket of β-secretase, right between two β strands. When the 10s loop takes an open conformation, it allows for greater binding between the substrate and the S3 pocket. The 10s loop also contains within it a that can hydrogen bond with the substrate, allowing for further stabilization of the 10s loop, as well as the overall β-secretase-substrate interaction.
The three parts come together to form a sort of binding pocket for β-secretase's substrates or inhibitors. Binding to the active site activates the flap to close and initiates binding by the 10s loop, all to help stabilize the structure.
Alzheimer's Disease
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:
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.
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.
Inhibition of Beta Secretase
References
Proteopedia Page Contributors and Editors (what is this?)
Michal Harel, Alexander Berchansky, Daniel Santos, Jaime Prilusky, Joel L. Sussman, David Canner
