APH-1 (anterior pharynx-defective 1) is a

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 ...

originally identified in the round worm ''

Caenorhabditis elegans ''Caenorhabditis elegans'' () is a free-living transparent nematode about 1 mm in length that lives in temperate soil environments. It is the type species of its genus. The name is a Hybrid word, blend of the Greek ''caeno-'' (recent), ''r ...

'' as a regulator of the cell-surface localization of

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 ...

in the

Notch signaling pathway The Notch signaling pathway is a highly Conserved sequence, conserved cell signaling system present in most animal, animals. Mammals possess four different Notch proteins, notch receptors, referred to as NOTCH1, NOTCH2, Notch 3, NOTCH3, and NOTC ...

. APH-1 homologs in other organisms, including humans ( APH1A and APH1B), have since been identified as components of 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 along with the catalytic subunit

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 ons ...

and the regulatory subunits

and

PEN-2 PSENEN, 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 pathway, Notch protein and amylo ...

. The gamma-secretase complex is a multimeric

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 ...

responsible for the intramembrane

proteolysis 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 ...

transmembrane protein A transmembrane protein is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequently un ...

s such as the Notch protein and

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). Gamma-secretase cleavage of APP is one of two proteolytic steps required to generate the

peptide Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty am ...

known as

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 ...

, whose misfolded form is implicated in the causation 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 ...

. All of the components of the gamma-secretase complex undergo extensive

post-translational modification In molecular biology, post-translational modification (PTM) is the covalent process of changing proteins following protein biosynthesis. PTMs may involve enzymes or occur spontaneously. Proteins are created by ribosomes, which translation (biolog ...

, 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 An alpha helix (or α-helix) is a sequence of amino acids in a protein that are twisted into a coil (a helix). The alpha helix is the most common structural arrangement in the Protein secondary structure, secondary structure of proteins. It is al ...

interaction motif

glycine Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid. Glycine is one of the proteinogenic amino acids. It is encoded by all the codons starting with GG (G ...

-X-X-X-

( GXXXG) that is essential to both assembly of the gamma secretase complex and to the maturation of the components.

Alternative splicing

In humans, the genes APH1A and APH1B encode the APH-1 proteins, which are integral components of the gamma-secretase complex, a multi-protein complex essential for the intramembrane cleavage of various substrates, including the

(APP) and Notch receptors. APH1A is located on chromosome 1q21.2, while APH1B is found on chromosome 15q22.2. Both genes exhibit alternative splicing, leading to the generation of multiple transcript variants that enhance the functional diversity of 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. The alternative splicing of APH1A and APH1B contributes significantly to the regulation of

activity. Studies have shown that different isoforms of APH1 can modulate the cleavage of APP, influencing the production of amyloid-beta peptides, which are implicated in Alzheimer's disease. Moreover, the expression levels of these isoforms can vary in different tissues and under various pathological conditions, suggesting a complex regulatory mechanism that may have implications for diseases such as cancer and neurodegeneration. The involvement of APH1A and APH1B in the

further underscores their importance in developmental processes and cellular fate decisions, which can be disrupted in various cancers. The functional versatility provided by the alternative splicing of APH1A and APH1B is crucial for the

complex's role in cellular signaling and proteolytic processing. For example, APH1A has been shown to be critical for the activity of the gamma-secretase complex, and its alternative splicing can influence the complex's substrate specificity and cleavage efficiency. Additionally, the interplay between APH1 isoforms and other components of the gamma-secretase complex, such as presenilins and

, is essential for maintaining the proper function of this protease.

Differences between APH1A and APH1B

Expression patterns

APH1A and APH1B, while homologous, exhibit distinct expression patterns across various tissues. APH1A is known for its ubiquitous expression, with significantly higher levels observed in the brain, heart, and skeletal muscle. In contrast, APH1B displays a more restricted expression profile, being predominantly expressed in the brain and testis. This differential expression suggests that APH1A may play a more generalized role in cellular processes, while APH1B could be more specialized, particularly in neural and reproductive tissues. Recent studies have highlighted the potential of APH1B as a peripheral biomarker for

(AD). Specifically, dysregulated expression levels of APH1B in peripheral blood have been associated with brain atrophy and amyloid-β deposition in AD patients. This association indicates that APH1B could serve as a valuable indicator of disease progression, providing insights into the underlying pathological mechanisms of AD.

Gamma-secretase activity

Functional studies have demonstrated that APH1A- and APH1B-containing

complexes exhibit distinct effects on enzyme activity and substrate processing. Notably, complexes containing APH1B have been shown to produce higher amounts of amyloid-beta 42 (Aβ42), a peptide closely linked to the pathology of

, compared to those containing APH1A. This difference in Aβ42 production is significant, as elevated levels of this peptide are associated with the formation of amyloid plaques, a hallmark of AD. The variations in substrate specificity and activity between the two isoforms could influence critical biological processes, including the processing of

(APP) and Notch signaling pathways. For instance, studies suggest that the presence of APH1B may lead to a shift in the cleavage patterns of APP, potentially favoring the production of longer and more pathogenic Aβ species. This altered processing could have profound implications for neuronal health and the progression of neurodegenerative diseases.

Structure

APH-1 proteins, which include APH1A and APH1B, are classified as polytopic membrane proteins characterized by the presence of seven

transmembrane domains A transmembrane domain (TMD, TM domain) is a membrane-spanning protein domain. TMDs may consist of one or several alpha-helices or a transmembrane beta barrel. Because the interior of the lipid bilayer is hydrophobic, the amino acid residues in ...

(TMDs). This structural feature is crucial for their integration into cellular membranes and their interaction with other components of the

complex. The topology of APH-1 enables it to span the

lipid bilayer The lipid bilayer (or phospholipid bilayer) is a thin polar membrane made of two layers of lipid molecules. These membranes form a continuous barrier around all cell (biology), cells. The cell membranes of almost all organisms and many viruses a ...

multiple times, effectively creating a scaffold that supports the assembly and stability of the gamma-secretase complex. The seven TMDs of APH-1 facilitate its proper localization within the membrane, allowing it to interact with other integral membrane proteins, such as

and

, which are also essential components of the

complex. The arrangement of these transmembrane domains is vital for the functional integrity of the complex, as it influences the accessibility of substrates and the catalytic activity of the gamma-secretase. In addition to the transmembrane domains, APH-1 proteins contain a conserved GXXXG motif within their transmembrane regions. This motif is critical for mediating helix-helix interactions that are essential for the assembly of the gamma-secretase complex. The GXXXG motif facilitates the dimerization of transmembrane helices, promoting the stability and functionality of the protein complex. Furthermore, APH-1 contains other conserved sequences that play significant roles in maintaining the protein's stability and facilitating interactions with nicastrin and presenilin. These structural motifs and domains are not only important for the assembly of the gamma-secretase complex but also for its enzymatic activity. The interactions between APH-1 and other components are crucial for the proper processing of substrates, including

(APP) and Notch receptors, which are involved in critical cellular signaling pathways.

Regulation of expression

Transcriptional

The expression of APH-1 genes, which include APH1A and APH1B, is regulated by several transcription factors and signaling pathways. One significant pathway involved in this regulation is the

, which can modulate the expression of APH-1, creating a feedback loop that adjusts gamma-secretase activity according to cellular needs. This interaction underscores the importance of APH-1 in cellular signaling and its potential role in maintaining homeostasis within the

complex. Additionally, factors such as

hypoxia-inducible factor Hypoxia-inducible factors (HIFs) are transcription factors that respond to decreases in available oxygen in the cellular environment, or hypoxia. They also respond to instances of pseudohypoxia, such as thiamine deficiency. Both hypoxia an ...

(HIF) have been shown to influence APH-1 expression under specific physiological conditions, particularly in response to low oxygen levels. This suggests that APH-1 may play a role in cellular adaptation to hypoxic environments, further emphasizing its regulatory complexity.

Post-translational modifications

Post-translational modifications In molecular biology, post-translational modification (PTM) is the covalent process of changing proteins following protein biosynthesis. PTMs may involve enzymes or occur spontaneously. Proteins are created by ribosomes, which translation (biolog ...

(PTMs) of APH-1, including

glycosylation Glycosylation is the reaction in which a carbohydrate (or ' glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not ...

and

phosphorylation In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writ ...

, significantly affect the protein's stability, localization, and interactions within the

complex. Glycosylation, for instance, is a major PTM that can influence protein folding, stability, and interactions with other proteins. The addition of carbohydrate moieties can affect how APH-1 interacts with other components of the gamma-secretase complex, thereby impacting its overall function.

Phosphorylation In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writ ...

is another critical PTM that can modulate APH-1 activity. It has been shown that phosphorylation can alter protein conformation, localization, and interaction dynamics, which are essential for the proper functioning of the

complex. The interplay between different types of PTMs can create a complex regulatory network that fine-tunes APH-1 activity in response to various cellular signals and conditions.

Clinical significance

Altered expression of APH-1 genes has been investigated in the context of

and other neurological disorders. Variations in these genes may modulate disease risk or progression by affecting

activity and

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 ...

production. Elevated expression of APH1B in peripheral blood has been associated with brain atrophy and increased amyloid-β deposition in Alzheimer's patients, indicating its potential as a biomarker.

As a drug target

Targeting APH-1 offers a potential therapeutic avenue for modulating gamma-secretase activity without completely inhibiting its function. Small molecules or peptides that specifically disrupt APH-1 interactions within the complex could reduce

production while minimizing side effects. Modulating the composition of the

complex to favor APH1A over APH1B may reduce the production of neurotoxic Aβ42 species.

References

External links

* {{MeshName, APH-1+protein,+human Alzheimer's disease Proteins