Protein pigeon homolog also known as gamma-secretase activating protein (GSAP) is a

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, respo ...

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

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 ba ...

Gene

The human ''PION'' gene is located on the long (q) arm of

chromosome 7 Chromosome 7 is one of the 23 pairs of chromosomes in humans, who normally have two copies of this chromosome. Chromosome 7 spans about 159 million base pairs (the building material of DNA) and represents between 5 and 5.5 percent of the total DN ...

at band 11.23, from

base pair A base pair (bp) is a fundamental unit of double-stranded nucleic acids consisting of two nucleobases bound to each other by hydrogen bonds. They form the building blocks of the DNA double helix and contribute to the folded structure of both DNA ...

76,778,007 to base pair 76,883,653. Highly conserved ''PION''

orthologs Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a spec ...

have been identified in most

vertebrates Vertebrates () comprise all animal taxa within the subphylum Vertebrata () ( chordates with backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the phylum Chordata, ...

for which complete genome data are available. More distantly related orthologs are also expressed in insects including the ''pigeon'' gene in ''

Drosophila melanogaster ''Drosophila melanogaster'' is a species of fly (the taxonomic order Diptera) in the family Drosophilidae. The species is often referred to as the fruit fly or lesser fruit fly, or less commonly the "vinegar fly" or "pomace fly". Starting with Ch ...

'' that when mutated produces the "pigeon"

phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological proper ...

. The name of the human ''PION'' gene derives the corresponding ''Drosophila'' gene.

Protein

The transcribed human pigeon homolog protein is 854

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

residues in length.

UniProt UniProt is a freely accessible database of protein sequence and functional information, many entries being derived from genome sequencing projects. It contains a large amount of information about the biological function of proteins derived from ...

: A 16 k Da fragment (GSAP-16K) derived from 121 residues from the

C-terminus The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...

region of the full length protein is known as the γ-secretase activating protein (GSAP).

Function

γ-secretase activating protein (GSAP) increases

β-amyloid Amyloid beta (Aβ or Abeta) 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 precursor protein (APP), which is ...

production through a mechanism involving its interactions with both γ-secretase and its substrate, 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 ...

(APP). * By binding to both the γ-secretase enzyme and its APP substrate, GSAP increases the affinity and the selectivity of the enzyme for this particular substrate.

Therapeutic target for Alzheimer's disease

The activating function of GSAP can be inhibited by the anticancer drug

imatinib Imatinib, sold under the brand names Gleevec and Glivec (both marketed worldwide by Novartis) among others, is an oral chemotherapy medication used to treat cancer. Imatinib is a small molecule inhibitor targeting multiple receptor tyrosine kin ...

(Gleevec) which in turn prevents γ-secretase from converting APP into plaque forming β-amyloid without affecting the other functions of γ-secretase. Imatinib itself does not get into the brain so imatinib could not be used as an AD therapeutic. However it may be possible to identify imatinib-like drugs that do get into the brain. Hence GSAP represents a potential therapeutic target for the treatment of

Alzheimer's disease Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...

(AD). The drug

semagacestat Semagacestat (LY-450139) was a candidate drug for a causal therapy against Alzheimer's disease. It was originally developed by Eli Lilly and Elan, and clinical trials were conducted by Eli Lilly. Phase III trials included over 3000 patients, but ...

in contrast to imatinib, works by directly inhibiting the γ-secretase. While semagacestat reduces β-amyloid plaque formation in AD patients, γ-secretase is also needed to make other important proteins. The failure of semagacestat to improve the

cognitive function Cognitive skills, also called cognitive functions, cognitive abilities or cognitive capacities, are brain-based skills which are needed in acquisition of knowledge, manipulation of information and reasoning. They have more to do with the mechanisms ...

of AD patients may be due to its non-selective blockade of γ-secretase. The more selective blockade of γ-secretase provided by inhibiting GSAP may make GSAP a more efficacious and safer drug target than γ-secretase.

Discovery

The ''PION'' gene was originally discovered through a large scale

genome sequencing Whole genome sequencing (WGS), also known as full genome sequencing, complete genome sequencing, or entire genome sequencing, is the process of determining the entirety, or nearly the entirety, of the DNA sequence of an organism's genome at a ...

effort. However the function of the ''PION'' gene product remained a mystery. In the laboratory of

Paul Greengard Paul Greengard (December 11, 1925 – April 13, 2019) was an American neuroscientist best known for his work on the molecular and cellular function of neurons. In 2000, Greengard, Arvid Carlsson and Eric Kandel were awarded the Nobel Prize for Ph ...

, a screen of compounds that could inhibit the formation of β-amyloid identified imatinib, however it was not immediately known how it accomplished this. Later it was discovered by Greengard's lab that imatinib inhibited the function of GSAP and that GSAP in turn functions as an activator of γ-secretase.

Gene

Protein

Function

Therapeutic target for Alzheimer's disease

Discovery

References

Further reading