Secretases are enzymes that "snip" pieces off a longer protein

Protein

Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

 that is embedded in the cell membrane

Cell membrane

The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...

. Among other roles in the cell

Cell (biology)

The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....

, secretases act on the amyloid precursor protein

Amyloid precursor protein

Amyloid precursor protein is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. Its primary function is not known, though it has been implicated as a regulator of synapse formation, neural plasticity and iron export...

 (APP) to cleave the protein into three fragments. Sequential cleavage by β-secretase

Beta-secretase

Beta-secretase 1 also known as beta-site APP cleaving enzyme 1 , memapsin-2 , and aspartyl protease 2 is an enzyme that in humans is encoded by the BACE1 gene.β-Secretase is an aspartic-acid protease important in the pathogenesis of Alzheimer's disease,...

 (BACE) and γ-secretase produces the amyloid-β peptide fragment that aggregates into clumps called "plaques" in the brain

Brain

The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...

s of Alzheimer's disease

Alzheimer's disease

Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...

 patients. If α-secretase acts on APP first instead of BACE, no amyloid-β 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

Protein structure

Proteins are an important class of biological macromolecules present in all organisms. Proteins are polymers of amino acids. Classified by their physical size, proteins are nanoparticles . Each protein polymer – also known as a polypeptide – consists of a sequence formed from 20 possible L-α-amino...

 of the three secretases varies widely.

• The α-secretase gene
  Gene
  A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
  
   has not been conclusively identified but is believed to be a metalloproteinase
  Metalloproteinase
  Metalloproteinases constitute a family of enzymes from the group of proteases, classified by the nature of the most prominent functional group in their active site. These are proteolytic enzymes whose catalytic mechanism involves a metal. Most metalloproteases are zinc-dependent, but some use...
  
  .

• BACE is a transmembrane protein with an extracellular aspartic acid protease domain
  Domain (biology)
  In biological taxonomy, a domain is the highest taxonomic rank of organisms, higher than a kingdom. According to the three-domain system of Carl Woese, introduced in 1990, the Tree of Life consists of three domains: Archaea, Bacteria and Eukarya...
  
  .

• γ-secretase is actually a protein complex
  Protein complex
  A multiprotein complex is a group of two or more associated polypeptide chains. If the different polypeptide chains contain different protein domain, the resulting multiprotein complex can have multiple catalytic functions...
  
   containing presenilin
  Presenilin
  Presenilins are a family of related multi-pass transmembrane proteins that function as a part of the gamma-secretase intramembrane protease complex...
  
  , nicastrin
  Nicastrin
  Nicastrin, also known as NCSTN, is a protein which in humans is encoded by the NCSTN gene.Nicastrin is a protein that is part of the gamma secretase protein complex, which is one of the proteases involved in processing amyloid precursor protein to the short Alzheimer's disease-associated peptide...
  
  , ACH-1, and PEN-2
  PEN-2
  PEN-2 is a protein that is a regulatory component of the gamma secretase complex, a protease complex responsible for proteolysis of transmembrane proteins such as the Notch protein and amyloid precursor protein . The gamma secretase complex consists of PEN-2, APH-1, nicastrin, and the catalytic...
  
  . Presenilin is believed to harbor the protease domain and represents an important example of an uncommon type of protease
  Protease
  A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....
  
   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

Signal transduction

Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...

 by the transmembrane receptor Notch

Notch signaling

The notch signaling pathway is a highly conserved cell signaling system present in most multicellular organisms.Notch is present in all metazoans, and mammals possess four different notch receptors, referred to as NOTCH1, NOTCH2, NOTCH3, and NOTCH4. The notch receptor is a single-pass...

, freeing the cytoplasmic tail of Notch to travel to the cell nucleus

Cell nucleus

In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...

 to act as a transcription factor

Transcription factor

In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...

.

Although BACE cleaves the extracellular domains of several transmembrane proteins, its physiological function remains unknown.