Presenilin-1 (PS-1) is a presenilin

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

that in humans is encoded by the ''PSEN1''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. Presenilin-1 is one of the four core proteins in the

gamma secretase Gamma secretase is a multi-subunit protease complex, 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. The most ...

complex, which is considered to play an important role in generation of

amyloid beta Amyloid beta (Aβ, Abeta or beta-amyloid) denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid-beta precursor prot ...

(Aβ) from

amyloid-beta precursor protein Amyloid-beta precursor protein (APP) is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. It functions as a cell surface receptor and has been implicated as a regulator of synapse formation, ...

(APP). Accumulation of amyloid beta is associated with the onset of

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

Structure

Presenilin possesses a 9 transmembrane domain topology, with an

extracellular This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...

C-terminus The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein Proteins are large biomolecules and macromolecules that comp ...

and a

cytosolic The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...

N-terminus The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...

. Presenilin undergoes endo-

proteolytic Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Protein degradation is a major regulatory mechanism of gene expression and contributes substantially to shaping mammalian proteomes. Uncatalysed, the hydrolysis o ...

processing to produce ~27-28

kDa The dalton or unified atomic mass unit (symbols: Da or u, respectively) is a unit of mass defined as of the mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state and at rest. It is a non-SI unit accepted f ...

N-terminal and ~16-17 kDa C-terminal fragments in humans. Furthermore, presenilin exists in the cell mainly as a

heterodimer In biochemistry, a protein dimer is a macromolecular complex or multimer formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ...

of the C-terminal and N-terminus fragments. When presenilin 1 is overexpressed, the full length protein accumulates in an inactive form. Based on evidence that a gamma-secretase inhibitor binds to the fragments, the cleaved presenilin complex is considered to be the active form.

Function

Presenilins are postulated to regulate APP processing through their effects on

, an enzyme that cleaves APP. Also, it is thought that the presenilins are involved in the cleavage of the

Notch receptor __NOTOC__ __FORCETOC__ Notch proteins are a Protein family, family of type 1 transmembrane proteins that form a core component of the Notch signaling pathway, which is highly conserved in Animal, animals. The Notch extracellular domain mediates i ...

, such that they either directly regulate

activity or themselves are

protease A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalysis, catalyzes proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the formation of new protein products ...

enzymes. Multiple alternatively spliced transcript variants have been identified for this gene, the full-length natures of only some have been determined.

Notch signaling pathway

In Notch signaling, critical proteolytic reactions takes place during maturation and activation of Notch membrane receptor. Notch1 is cleaved extracellularlly at site1 (S1) and two polypeptides are produced to form a heterodimer receptor on the cell surface. After the formation of receptor, Notch1 is further cleaved in site 3(S3) and release Notch1 intracellular domain (NICD) from the membrane. Presenilin 1 has been shown to play an important role in proteolytic process. In the prenilin 1 null mutant drosophila, Notch signaling is abolished and it displays a notch-like lethal phenotype. Moreover, in mammalian cells, deficiency of PSEN1 also causes the defect in the proteolytic release of NICD from a truncated Notch construct. The same step can be also blocked by several gamma-secretase inhibitors, shown in the same study. These evidences collectively suggest a critical role of presenilin 1 in the Notch signaling pathway.

Wnt signaling pathway

Wnt signaling pathway In cellular biology, the Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt, pronounced "wint", is a portmanteau created from the ...

has been shown to be involved in several critical steps in embryogenesis and development. Presenilin 1 has been shown to form a complex with

beta-catenin Catenin beta-1, also known as β-catenin (''beta''-catenin), is a protein that in humans is encoded by the ''CTNNB1'' gene. β-Catenin is a dual function protein, involved in regulation and coordination of cell–cell adhesion and gene transcrip ...

, an important component in Wnt signaling, and stabilize beta-catenin. Mutant of presenilin-1 that reduces the ability to stabilize beta-catenin complex leads to hyperactive degradation of beta-catenin in the brains of transgenic mice. Considered as a negative regulator in Wnt signaling pathway, presenilin-1 was also found to play a role in beta-catenin phosphorylation. Beta-catenin is coupled by presenilin-1 and undergoes a sequential phosphorylation by two kinase activities. The study also further illustrates that the deficiency of presenilin 1 disconnects the sequential phosphorylation and thus disrupts the normal wnt signaling pathway.

Clinical significance

Beta-amyloid production

Transgenic mice that over-expressed mutant presenilin-1 show an increase of beta-amyloid-42(43) in the brain, which suggest presenilin-1 plays an important role in beta-amyloid regulation and can be highly related to Alzheimer's disease. Further study conducted in neuronal cultures derived from presenilin-1 deficient mouse embryos showed that cleavage by alpha- and beta- secretase was still normal without the presence of presenilin-1. Meanwhile, when the cleavage by gamma-cleavage of the transmembrane domain of APP was abolished a 5-fold drop of amyloid peptide was observed, suggesting that deficiency of presenilin-1 can downregulate amyloid and inhibition of presenilin-1 can be a potential method for anti-amyloidogenic therapy in Alzheimer's disease. Extensive study on the role of presenilin-1 in amyloid production has been conducted to improve our understanding of Alzheimer's disease.

Alzheimer's disease

(AD) patients with an inherited form of the disease may carry mutations in the presenilin proteins (PSEN1;

PSEN2 Presenilin-2 is a protein that (in humans) is encoded by the ''PSEN2'' gene. Function Alzheimer's disease (AD) patients with an inherited form of the disease carry mutations in the presenilin proteins ( PSEN1; PSEN2) or the amyloid precursor ...

) or the

amyloid precursor protein Amyloid-beta precursor protein (APP) is an integral membrane protein expressed in many biological tissue, tissues and concentrated in the synapses of neurons. It functions as a cell surface receptor and has been implicated as a regulator of s ...

(APP). These disease-linked mutations result in increased production of the longer form of

(main component of

amyloid Amyloids are aggregates of proteins characterised by a fibrillar morphology of typically 7–13 nm in diameter, a β-sheet secondary structure (known as cross-β) and ability to be stained by particular dyes, such as Congo red. In the human ...

deposits found in AD brains). These mutations result in early-onset Alzheimer's Disease, which is a rare form of the disease. These rare genetic variants are autosomal dominant.

Cancer

In addition to its role in Alzheimer's disease, presenilin-1 also found to be important in cancer. A study of broad range gene expression was conducted on human malignant

melanoma Melanoma is the most dangerous type of skin cancer; it develops from the melanin-producing cells known as melanocytes. It typically occurs in the skin, but may rarely occur in the mouth, intestines, or eye (uveal melanoma). In very rare case ...

. Researchers classified the malignant melanoma cell lines into two types. The study showed that presenilin-1 is down regulated in this cell type while it is overexpressed in the other cell type. Another study on multidrug resistance (MDR) cell line also reveals a role of presenilin-1 in cancer development. Because of the development to the resistance to chemicals, MDR cells become a critical factor on the success of cancer chemotherapy. In the study, researchers tried to explore the molecular mechanism by looking into the expression of Notch1 intracellular (N1IC) domain and presenilin 1. They found that there is higher level expression of both proteins and a multidrug resistance-associated protein 1 ( ABCC1) was also found to be regulated by N1IC, which suggest a mechanism of ABCC1 regulated by presenilin 1 and notch signaling.

Interactions

PSEN1 has been shown to interact with: *

BCL2 Bcl-2, encoded in humans by the ''BCL2'' gene, is the founding member of the apoptosis regulator proteins, Bcl-2 family, Bcl-2 family of regulator proteins. BCL2 blocks programmed cell death (apoptosis) while other BCL2 family members can eithe ...

, *

CTNNB1 Catenin beta-1, also known as β-catenin (''beta''-catenin), is a protein that in humans is encoded by the ''CTNNB1'' gene. β-Catenin is a dual function protein, involved in regulation and coordination of cell–cell adhesion and gene transcr ...

, *

CTNND1 p120 catenin, or simply p120, also called catenin delta-1, is a protein that in humans is encoded by the ''CTNND1'' gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a se ...

, *

FLNB Filamin B, beta (FLNB), also known as Filamin B, beta (truncated actin binding protein 278 homolog), is a cytoplasmic protein which in humans is encoded by the ''FLNB'' gene. FLNB regulates intracellular communication and signalling by cross-link ...

, * GFAP, *

Delta catenin Delta commonly refers to: * Delta (letter) (Δ or δ), the fourth letter of the Greek alphabet * D (NATO phonetic alphabet: "Delta"), the fourth letter in the Latin alphabet * River delta, at a river mouth * Delta Air Lines, a major US carrier ...

, *

ICAM5 Intercellular adhesion molecule 5 is a protein that in humans is encoded by the ''ICAM5'' gene. The protein encoded by this gene is a member of the intercellular adhesion molecule (ICAM) family. All ICAM proteins are type I transmembrane glycopro ...

, * KCNIP3, * NCSTN, *

PKP4 Plakophilin-4 is a protein that in humans is encoded by the ''PKP4'' gene. Function Armadillo-like proteins are characterized by a series of armadillo repeats, first defined in the Drosophila 'armadillo' gene product, that are typically 42 to ...

, and *

UBQLN1 Ubiquilin-1 is a protein that in humans is encoded by the ''UBQLN1'' gene. Ubiquilins contain two domains, an N-terminal ubiquitin-like domain and a C-terminal ubiquitin-associated domain. They physically associate with both proteasomes and u ...

References

External links

GeneReviews/NCBI/NIH/UW entry on Early-Onset Familial Alzheimer Disease
{{Membrane proteins Alzheimer's disease