Secretases are
enzymes
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
that "snip" pieces off a longer
protein that is embedded in the
cell membrane.
300px, Processing of the amyloid-beta precursor protein Among other roles in the
cell, secretases act on the
amyloid-beta precursor protein (APP) to cleave the protein into three fragments. Sequential cleavage by
beta-secretase 1 (BACE) and
gamma-secretase (γ-secretase) produces the
amyloid-beta peptide fragment that aggregates into clumps called
amyloid plaques
Amyloid plaques (also known as neuritic plaques, amyloid beta plaques or senile plaques) are extracellular deposits of the amyloid beta (Aβ) protein mainly in the grey matter of the brain. Degenerative neuronal elements and an abundance of micr ...
in the
brains affected by
Alzheimer's disease
Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
. If
alpha-secretase (α-secretase) acts on APP first instead of BACE, no amyloid beta is formed because α-secretase recognizes a target
protein sequence closer to the cell surface than BACE. The non-pathogenic middle fragment formed by an α/γ cleavage sequence is called P3.
Structure
The
structure
A structure is an arrangement and organization of interrelated elements in a material object or system, or the object or system so organized. Material structures include man-made objects such as buildings and machines and natural objects such as ...
of the three secretases varies widely.
* The α-secretase
gene has not been conclusively identified but is believed to be a
metalloproteinase.
* BACE is a transmembrane protein with an extracellular
aspartic acid protease domain
Domain may refer to:
Mathematics
*Domain of a function, the set of input values for which the (total) function is defined
**Domain of definition of a partial function
**Natural domain of a partial function
**Domain of holomorphy of a function
* Do ...
.
* γ-secretase is actually a
protein complex containing
presenilin
Presenilins are a family of related multi-pass transmembrane proteins which constitute the catalytic subunits of the gamma-secretase intramembrane protease protein complex. They were first identified in screens for mutations causing early onset ...
,
nicastrin
Nicastrin, also known as NCSTN, is a protein that in humans is encoded by the ''NCSTN'' gene.
Function
Nicastrin (abbreviated NCT) is a protein that is part of the gamma secretase protein complex, which is one of the proteases involved in processi ...
,
APH-1, and
PEN-2. Presenilin is believed to harbor the protease domain and represents an important example of an uncommon type of
protease that cleaves targets within the cell membrane.
Function
Besides their involvement in the pathogenesis of Alzheimer's, these proteins also have other functional roles in the cell.
γ-secretase plays a critical role in
developmental signalling by the
transmembrane receptor Notch, freeing the
cytoplasmic
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. Th ...
tail of Notch to travel to the
cell nucleus
The cell nucleus (pl. nuclei; from Latin or , meaning ''kernel'' or ''seed'') is a membrane-bound organelle found in eukaryotic cells. Eukaryotic cells usually have a single nucleus, but a few cell types, such as mammalian red blood cells, h ...
to act as a
transcription factor.
Although BACE cleaves the extracellular domains of several transmembrane proteins, its physiological function remains unknown.
References
External links
*
{{Proteases
Enzymes
Integral membrane proteins
