Protein pigeon homolog
Encyclopedia
Protein pigeon homolog also known as gamma-secretase activating protein (GSAP) is a protein
that in humans is encoded by the PION gene
.
at band 11.23, from base pair
76,778,007 to base pair 76,883,653. Highly conserved PION orthologs have been identified in most vertebrates for which complete genome data are available. More distantly related orthologs are also expressed in insects including the pigeon gene in Drosophila melanogaster
that when mutated produces the "pigeon" phenotype
. The name of the human PION gene derives the corresponding Drosophila gene.
residues in length. A 16 kDa
fragment (GSAP-16K) derived from 121 residues from the C-terminus region of the full length protein is known as the γ-secretase activating protein (GSAP).
and its substrate, the amyloid precursor protein
(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.
(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
(AD).
The drug semagacestat
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
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.
effort. However the function of the PION gene product remained a mystery. In the laboratory of Paul Greengard
, 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.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the PION gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
Gene
The human PION gene is located on the long (q) arm of chromosome 7Chromosome 7 (human)
Chromosome 7 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 7 spans more than 158 million base pairs and represents between 5 and 5.5 percent of the total DNA in cells.Identifying genes on each chromosome is an active area of genetic...
at band 11.23, from base pair
Base pair
In molecular biology and genetics, the linking between two nitrogenous bases on opposite complementary DNA or certain types of RNA strands that are connected via hydrogen bonds is called a base pair...
76,778,007 to base pair 76,883,653. Highly conserved PION orthologs have been identified in most vertebrates 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
Drosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is known generally as the common fruit fly or vinegar fly. Starting from Charles W...
that when mutated produces the "pigeon" phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
. The name of the human PION gene derives the corresponding Drosophila gene.
Protein
The transcribed human pigeon homolog protein is 854 amino acidAmino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
residues in length. A 16 kDa
Atomic mass unit
The unified atomic mass unit or dalton is a unit that is used for indicating mass on an atomic or molecular scale. It is defined as one twelfth of the rest mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state, and has a value of...
fragment (GSAP-16K) derived from 121 residues from the C-terminus region of the full length protein is known as the γ-secretase activating protein (GSAP).
Function
γ-secretase activating protein (GSAP) increases β-amyloid production through a mechanism involving its interactions with both γ-secretaseGamma 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...
and its substrate, the amyloid precursor protein
Amyloid precursor protein
Amyloid precursor protein is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. Its primary function is not known, though it has been implicated as a regulator of synapse formation, neural plasticity and iron export...
(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 imatinibImatinib
Imatinib is a drug used to treat certain types of cancer. It is currently marketed by Novartis as Gleevec or Glivec as its mesylate salt, imatinib mesilate . It is used in treating chronic myelogenous leukemia , gastrointestinal stromal tumors and some other diseases...
(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
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
(AD).
The drug semagacestat
Semagacestat
Semagacestat was a candidate drug for a causal therapy against Alzheimer's disease. It was originally developed by Eli Lilly and Élan, and clinical trials were conducted by Eli Lilly...
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
Cognition
In science, cognition refers to mental processes. These processes include attention, remembering, producing and understanding language, solving problems, and making decisions. Cognition is studied in various disciplines such as psychology, philosophy, linguistics, and computer science...
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 sequencingFull genome sequencing
Full genome sequencing , also known as whole genome sequencing , complete genome sequencing, or entire genome sequencing, is a laboratory process that determines the complete DNA sequence of an organism's genome at a single time...
effort. However the function of the PION gene product remained a mystery. In the laboratory of Paul Greengard
Paul Greengard
Paul Greengard is 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 Physiology or Medicine for their discoveries concerning signal transduction in the nervous...
, 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.