Secretases are enzymes that "snip" pieces off a longer

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

that is embedded in the

cell membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...

. 300px, Processing of the amyloid-beta precursor protein Among other roles in the

cell Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Locations * Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery ...

, secretases act on the amyloid-beta precursor protein (APP) to cleave the protein into three fragments. Sequential cleavage by

beta-secretase 1 Beta-secretase 1, also known as beta-site amyloid precursor protein cleaving enzyme 1, beta-site APP cleaving enzyme 1 (BACE1), membrane-associated aspartic protease 2, memapsin-2, aspartyl protease 2, and ASP2, is an enzyme that in humans is enc ...

(BACE) and

gamma-secretase Gamma secretase is a multi-subunit protease complex, itself an integral membrane protein, that cleaves single-pass transmembrane proteins at residues within the transmembrane domain. Proteases of this type are known as intramembrane proteases. Th ...

(γ-secretase) produces the amyloid-beta peptide fragment that aggregates into clumps called amyloid plaques in the

brain A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a ve ...

s affected by Alzheimer's disease. 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 Protein primary structure is the linear sequence of amino acids in a peptide or protein. By convention, the primary structure of a protein is reported starting from the amino-terminal (N) end to the carboxyl-terminal (C) end. Protein biosynthes ...

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 of the three secretases varies widely. * The α-secretase

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

has not been conclusively identified but is believed to be a

metalloproteinase A metalloproteinase, or metalloprotease, is any protease enzyme whose catalytic mechanism involves a metal. An example is ADAM12 which plays a significant role in the fusion of muscle cells during embryo development, in a process known as myo ...

. * BACE is a transmembrane protein with an extracellular

aspartic acid protease Aspartic proteases are a catalytic type of protease enzymes that use an activated water molecule bound to one or more aspartate residues for catalysis of their peptide substrates. In general, they have two highly conserved aspartates in the active ...

domain. * γ-secretase is actually a

protein complex A protein complex or multiprotein complex is a group of two or more associated polypeptide chains. Protein complexes are distinct from multienzyme complexes, in which multiple catalytic domains are found in a single polypeptide chain. Protein ...

containing presenilin, nicastrin,

APH-1 APH-1 (anterior pharynx-defective 1) is a protein gene product originally identified in the Notch signaling pathway in '' Caenorhabditis elegans'' as a regulator of the cell-surface localization of nicastrin. APH-1 homologs in other organisms, ...

, and

PEN-2 PENSEN, formally PEN-2 (presenilin enhancer 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 ...

. Presenilin is believed to harbor the protease domain and represents an important example of an uncommon type of

protease A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...

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 Cell surface receptors (membrane receptors, transmembrane receptors) are receptors that are embedded in the plasma membrane of cells. They act in cell signaling by receiving (binding to) extracellular molecules. They are specialized integral me ...

Notch, freeing the cytoplasmic tail of Notch to travel to the cell nucleus to act as a

transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The f ...

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

References

External links

* {{Proteases Enzymes Integral membrane proteins