Presenilin

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Presenilin
6idf psen1 notch blue asp.png
Cryo-electron microscopy structure of the human presenilin-1 (orange) in complex with a fragment of one of its protein substrates, Notch (green). The two catalytic sites are shown in blue. Rendered from PDB: 6IDF ​. [1]
Identifiers
SymbolPresenilin
Pfam PF01080
Pfam clan CL0130
InterPro IPR001108
MEROPS A22
TCDB 1.A.54
OPM superfamily 244
OPM protein 4hyg
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
presenilin 1
(Alzheimer's disease 3)
Identifiers
Symbol PSEN1
Alt. symbolsAD3
NCBI gene 5663
HGNC 9508
OMIM 104311
RefSeq NM_000021
UniProt P49768
Other data
EC number 3.4.23.-
Locus Chr. 14 q24.3
Search for
Structures Swiss-model
Domains InterPro
presenilin 2
(Alzheimer's disease 4)
Identifiers
Symbol PSEN2
Alt. symbolsAD4
NCBI gene 5664
HGNC 9509
OMIM 600759
RefSeq NM_000447
UniProt P49810
Other data
EC number 3.4.23.-
Locus Chr. 1 q31-q42
Search for
Structures Swiss-model
Domains InterPro

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 forms of familial Alzheimer's disease by Peter St George-Hyslop. [2] Vertebrates have two presenilin genes, called PSEN1 (located on chromosome 14 in humans) that codes for presenilin 1 (PS-1) and PSEN2 (on chromosome 1 in humans) that codes for presenilin 2 (PS-2). [3] Both genes show conservation between species, with little difference between rat and human presenilins. The nematode worm C. elegans has two genes that resemble the presenilins and appear to be functionally similar, sel-12 and hop-1. [4]

Contents

Presenilins undergo cleavage in an alpha helical region of one of the cytoplasmic loops to produce a large N-terminal and a smaller C-terminal fragment that together form part of the functional protein. [5] Cleavage of presenilin 1 can be prevented by a mutation that causes the loss of exon 9, and results in loss of function. Presenilins play a key role in the modulation of intracellular Ca2+ involved in presynaptic neurotransmitter release and long-term potentiation induction. [6]

Structure

Presenilins are transmembrane proteins with nine alpha helices. Structures have been solved of the assembled gamma secretase complex by cryo-electron microscopy, demonstrating significant conformational flexibility in the structure of the presenilin subunit of the complex in response to ligand or inhibitor binding. [7] [1] Presenilins undergo autocatalytic proteolytic processing after expression, cleaving a cytoplasmic loop region between the sixth and seventh helices to produce a large N-terminal and a smaller C-terminal fragment. The two fragments remain in contact with each other in the mature protein. The two catalytic aspartate active site residues required for aspartyl protease activity are located in the sixth and seventh helices. [8]

The structure and membrane topology of presenilins was originally controversial when they were first discovered. The PSEN1 gene was predicted to contain ten trans-membrane domains; models agreed on the expected topology of the N-terminal fragment, but the structure of the C-terminal fragment was disputed. A 2006 study suggested a nine-pass transmembrane topology with cleavage and assembly into the gamma-secretase complex prior to insertion into the plasma membrane. [9] Solution NMR studies of the C-terminal fragment showed three helices likely to traverse the membrane, [5] [10] while X-ray crystallography studies of an archaeal homolog, [11] as well as cryo-electron microscopy of the human gamma-secretase complex, indicate nine transmembrane helices. [7] [1]

Function

Catalytic

Presenilins are the catalytic component of the gamma secretase intramembrane protease, a four-member protein complex consisting of presenilin, nicastrin, APH-1, and PEN-2. It has a very broad range of substrates for its proteolytic activity. Its substrates are hydrophobic single-pass transmembrane helices with relatively small extracellular regions. [12] [13] These substrates arise following ectodomain shedding. [13] Well over 100 different integral membrane proteins are processed by gamma-secretase. [8] The best-characterized gamma-secretase substrates are the Notch receptor and amyloid precursor protein (APP). [7] [13] Presenilins' role in the Notch signaling pathway is important in development; [14] mice that have the PS1 gene knocked out die early in development from developmental abnormalities similar to those found when notch is disrupted. [15] In conditional knockout mice where presenilin is only inactivated after early development, there is evidence that presenilins in their role as gamma-secretase components are important in the survival of neurons during aging. [14]

There are subtle and species-specific variations in the roles of presenilin-1 and presenilin-2 in assembled gamma-secretase complexes, with many studies suggesting a primary role for presenilin-1. [13] In humans, the two presenilins differ in subcellular localization, and may also be cell type and tissue-specific. [8]

Non-catalytic

Presenilins also have additional non-catalytic roles in other cellular signaling processes, including calcium homeostasis, lysosomal acidification, autophagy, and protein trafficking. [16] [17] [18] The proteins' role in calcium homeostasis in neurons has been a subject of interest. [19] The genetic inactivation of presenilins in hippocampal synapses has shown this selectively affects the long-term potentiation caused by theta with the inactivation in presynapse but not the postsynapse impairing short-term plasticity and synaptic facilitation. [6] The release of glutamate was also reduced in presynaptic terminals by processes that involve modulation of intracellular Ca2+ release. [6] This has been suggested to "represent a general convergent mechanism leading to neurodegeneration". [6]

Homologs have been identified and characterized in diverse eukaryotic organisms, including model organisms Drosophila melanogaster and Caenorhabditis elegans , plants such as Arabidopsis thaliana and Physcomitrella patens , and the slime mold Dictyostelium discoideum . [17] [18] In these functions presenilins are thought to play a role as scaffold proteins, considered likely to be the ancestral role of the protein family. [18]

Expression and distribution

Both human presenilins have widespread expression in the brain. The two proteins differ in subcellular localization, with PS1 expressed more broadly and present at the cell membrane, while PS2 is present mainly in late endosomes and lysosomes. [8] [20]

Association with Alzheimer's disease

Most cases of Alzheimer's disease are not hereditary. However, there is a small subset of cases that have an earlier age of onset and have a strong genetic element. In patients with Alzheimer's disease (autosomal dominant hereditary), mutations in the presenilin proteins (PSEN1; PSEN2) or the amyloid precursor protein (APP) can be found. The majority of these cases carry mutant presenilin genes. An important part of the disease process in Alzheimer's disease is the accumulation of Amyloid beta (Aβ) protein. To form Aβ, APP must be cut by two enzymes, beta secretases and gamma secretase. Presenilin is the sub-component of gamma secretase that is responsible for the cutting of APP.

Gamma secretase can cut APP at several points within a small region of the protein, which results in Aβ of various lengths. The lengths associated with Alzheimer's disease are 40 and 42 amino acids long. Aβ 42 is more likely to aggregate to form plaques in the brain than Aβ 40. Presenilin mutations lead to an increase in the ratio of Aβ 42 produced compared to Aβ 40, although the total quantity of Aβ produced remains constant. [21] This can come about by various effects of the mutations upon gamma secretase. [22]

Discovery

The genes for the presenilins were discovered in 1995 through linkage studies using mutations present in familial Alzheimer's disease cases. [2] Around the same time, the presenilin homolog in Caenorhabditis elegans , sel-12 , was independently identified as a contributor to Notch signaling. [23] Although the function of the protein products of these genes was not immediately apparent, it became clear from subsequent work that the mutations were associated with higher proportions of Aβ42 over the less amyloidogenic Aβ40. The role of presenilins as the catalytic component of the gamma secretase protein complex was established by the early 2000s. [24] [25]

Related Research Articles

<span class="mw-page-title-main">Notch signaling pathway</span> Series of molecular signals

The Notch signaling pathway is a highly conserved cell signaling system present in most animals. Mammals possess four different notch receptors, referred to as NOTCH1, NOTCH2, NOTCH3, and NOTCH4. The notch receptor is a single-pass transmembrane receptor protein. It is a hetero-oligomer composed of a large extracellular portion, which associates in a calcium-dependent, non-covalent interaction with a smaller piece of the notch protein composed of a short extracellular region, a single transmembrane-pass, and a small intracellular region.

<span class="mw-page-title-main">Amyloid beta</span> Group of peptides

Amyloid beta 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 protein (APP), which is cleaved by beta secretase and gamma secretase to yield Aβ in a cholesterol-dependent process and substrate presentation. Both neurons and oligodendrocytes produce and release Aβ in the brain, contributing to formation of amyloid plaques. Aβ molecules can aggregate to form flexible soluble oligomers which may exist in several forms. It is now believed that certain misfolded oligomers can induce other Aβ molecules to also take the misfolded oligomeric form, leading to a chain reaction akin to a prion infection. The oligomers are toxic to nerve cells. The other protein implicated in Alzheimer's disease, tau protein, also forms such prion-like misfolded oligomers, and there is some evidence that misfolded Aβ can induce tau to misfold.

<span class="mw-page-title-main">Amyloid-beta precursor protein</span> Mammalian protein found in humans

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, neural plasticity, antimicrobial activity, and iron export. It is coded for by the gene APP and regulated by substrate presentation. APP is best known as the precursor molecule whose proteolysis generates amyloid beta (Aβ), a polypeptide containing 37 to 49 amino acid residues, whose amyloid fibrillar form is the primary component of amyloid plaques found in the brains of Alzheimer's disease patients.

<span class="mw-page-title-main">Amyloid-beta precursor protein secretase</span> Type of enzyme

Secretases are enzymes that "snip" pieces off a longer protein that is embedded in the cell membrane.

<span class="mw-page-title-main">Beta-secretase 1</span> Enzyme

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 encoded by the BACE1 gene. Expression of BACE1 is observed mainly in neurons and oligodendrocytes.

<span class="mw-page-title-main">Gamma secretase</span> Type of protein

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 well-known substrate of gamma secretase is amyloid precursor protein, a large integral membrane protein that, when cleaved by both gamma and beta secretase, produces a short 37-43 amino acid peptide called amyloid beta whose abnormally folded fibrillar form is the primary component of amyloid plaques found in the brains of Alzheimer's disease patients. Gamma secretase is also critical in the related processing of several other type I integral membrane proteins, such as Notch, ErbB4, E-cadherin, N-cadherin, ephrin-B2, or CD44.

<span class="mw-page-title-main">Alpha secretase</span> Family of proteolytic enzymes

Alpha secretases are a family of proteolytic enzymes that cleave amyloid precursor protein (APP) in its transmembrane region. Specifically, alpha secretases cleave within the fragment that gives rise to the Alzheimer's disease-associated peptide amyloid beta when APP is instead processed by beta secretase and gamma secretase. The alpha-secretase pathway is the predominant APP processing pathway. Thus, alpha-secretase cleavage precludes amyloid beta formation and is considered to be part of the non-amyloidogenic pathway in APP processing. Alpha secretases are members of the ADAM family, which are expressed on the surfaces of cells and anchored in the cell membrane. Several such proteins, notably ADAM10, have been identified as possessing alpha-secretase activity. Upon cleavage by alpha secretases, APP releases its extracellular domain - a fragment known as APPsα - into the extracellular environment in a process known as ectodomain shedding.

<span class="mw-page-title-main">Nicastrin</span>

Nicastrin, also known as NCSTN, is a protein that in humans is encoded by the NCSTN gene.

APH-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, including humans, have since been identified as components of the gamma secretase complex along with the catalytic subunit presenilin and the regulatory subunits nicastrin and PEN-2. The gamma-secretase complex is a multimeric protease responsible for the intramembrane proteolysis of transmembrane proteins such as the Notch protein and amyloid precursor protein (APP). Gamma-secretase cleavage of APP is one of two proteolytic steps required to generate the peptide known as amyloid beta, whose misfolded form is implicated in the causation of Alzheimer's disease. All of the components of the gamma-secretase complex undergo extensive post-translational modification, especially proteolytic activation; APH-1 and PEN-2 are regarded as regulators of the maturation process of the catalytic component presenilin. APH-1 contains a conserved alpha helix interaction motif glycine-X-X-X-glycine (GXXXG) that is essential to both assembly of the gamma secretase complex and to the maturation of the components.

<span class="mw-page-title-main">PEN-2</span> Protein-coding gene in the species Homo sapiens

PSENEN, formally 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 (APP). The gamma secretase complex consists of PEN-2, APH-1, nicastrin, and the catalytic subunit presenilin. PEN-2 is a 101-amino acid integral membrane protein likely with a topology such that both the N-terminus and the C-terminus face first the lumen of the endoplasmic reticulum and later the extracellular environment. Biochemical studies have shown that a conserved sequence motif D-Y-L-S-F at the C-terminus, as well as the overall length of the C-terminal tail, is required for the formation of an active gamma secretase complex.

<span class="mw-page-title-main">Insulin-degrading enzyme</span> Enzyme found in humans

Insulin-degrading enzyme, also known as IDE, is an enzyme.

<span class="mw-page-title-main">Presenilin-1</span> Protein-coding gene in the species Homo sapiens

Presenilin-1(PS-1) is a presenilin protein that in humans is encoded by the PSEN1 gene. Presenilin-1 is one of the four core proteins in the gamma secretase complex, which is considered to play an important role in generation of amyloid beta (Aβ) from amyloid-beta precursor protein (APP). Accumulation of amyloid beta is associated with the onset of Alzheimer's disease.

<span class="mw-page-title-main">Presenilin-2</span> Protein-coding gene in the species Homo sapiens

Presenilin-2 is a protein that is encoded by the PSEN2 gene.

<span class="mw-page-title-main">TMED10</span> Protein-coding gene

Transmembrane emp24 domain-containing protein 10 is a protein that in humans is encoded by the TMED10 gene.

<span class="mw-page-title-main">SPPL2B</span> Protein-coding gene in the species Homo sapiens

Signal peptide peptidase-like 2B, also known as SPPL2B, is a human gene.

<span class="mw-page-title-main">PARL</span> Protein-coding gene in the species Homo sapiens

Presenilins-associated rhomboid-like protein, mitochondrial (PSARL), also known as PINK1/PGAM5-associated rhomboid-like protease (PARL), is an inner mitochondrial membrane protein that in humans is encoded by the PARL gene on chromosome 3. It is a member of the rhomboid family of intramembrane serine proteases. This protein is involved in signal transduction and apoptosis, as well as neurodegenerative diseases and type 2 diabetes.

Early-onset Alzheimer's disease (EOAD), also called younger-onset Alzheimer's disease (YOAD), is Alzheimer's disease diagnosed before the age of 65. It is an uncommon form of Alzheimer's, accounting for only 5–10% of all Alzheimer's cases. About 60% have a positive family history of Alzheimer's and 13% of them are inherited in an autosomal dominant manner. Most cases of early-onset Alzheimer's share the same traits as the "late-onset" form and are not caused by known genetic mutations. Little is understood about how it starts.

<span class="mw-page-title-main">Protein pigeon homolog</span> Protein-coding gene in the species Homo sapiens

Protein pigeon homolog also known as gamma-secretase activating protein (GSAP) is a protein that in humans is encoded by the PION gene.

Intramembrane proteases (IMPs), also known as intramembrane-cleaving proteases (I-CLiPs), are enzymes that have the property of cleaving transmembrane domains of integral membrane proteins. All known intramembrane proteases are themselves integral membrane proteins with multiple transmembrane domains, and they have their active sites buried within the lipid bilayer of cellular membranes. Intramembrane proteases are responsible for proteolytic cleavage in the cell signaling process known as regulated intramembrane proteolysis (RIP).

<span class="mw-page-title-main">P3 peptide</span>

p3 peptide also known as amyloid β- peptide (Aβ)17–40/42 is the peptide resulting from the α- and γ-secretase cleavage from the amyloid precursor protein (APP). It is known to be the major constituent of diffuse plaques observed in Alzheimer's disease (AD) brains and pre-amyloid plaques in people affected by Down syndrome. However, p3 peptide's role in these diseases is not truly known yet.

References

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  10. ↑ PDB: 2KR6 ​; Doetsch V (2010). "Solution structure of presenilin-1 CTF subunit". Worldwide Protein Data Bank. doi:10.2210/pdb2kr6/pdb.
  11. ↑ Li X, Dang S, Yan C, Gong X, Wang J, Shi Y (January 2013). "Structure of a presenilin family intramembrane aspartate protease". Nature. 493 (7430): 56–61. Bibcode:2013Natur.493...56L. doi:10.1038/nature11801. PMID   23254940. S2CID   4429356.
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