Function
As a homeodomain protein it plays a key role in developing adult organisms. It is a transcription factor that leads to the activation of gene promoters and allows them to execute transcription. PITX1, along with the other homeodomain proteins, have a specific DNA binding. It evidently resides in the nucleus, and as a transcription factor it binds to DNA and is sequence-specific in its binding. As a transcription factor it can promote or enhance specific genes and has an effect on RNA polymerase II. It regulates the mRNA produced by the PITX1 gene as well. It activates the transcription of a variety of pituitary genes.
The PITX1 protein and the PITX2 protein are each some of the first transcription factors that are in pituitary glands. They are bicoid proteins as they can affect the maternal gene and then have effects on fetal development. The two transcription factors are first in progenitor cells as Rathke’s pouch is being formed. PITX1 can increase the expression of some genes. In mice it had been studied that if mice had completely lost all their PITX1 proteins then there would be some cells in the pituitary that are much more prevalent than others and some that completely lose prevalence in the pituitary. This proves how the PITX1 protein has a vital role in balancing the pituitary. It was found in 1999, to be important for gonadotropes and their transcription. PITX1 is most common in a specific pituitary cell and this type of cell includes genes that are in glycoprotein hormone subunit alpha as well as luteinizing hormone beta. How PITX1 interacts with cell-restricting factors is what makes its interactions so specific. It interacts with many cell-restricting factors which gives it the ability to activate prolactin and growth hormones. In corticotrope cells it interacts with basic helix-loop-helix heterodimer to activate the pro-opiomelancortin promoter. This all further proves how PITX1 is intricate in how it interacts with other molecules to act as a transcription factor.
Disease
The PITX1 protein can have effects on humans if the gene is affected. It has been studied in causing club foot, polydactyly and autism due to a missense mutation. A missense mutation is where a single nucleotide is altered and affects a codon, which codes for another amino acid. Club foot is a congenital limb disorder where both feet are curved and rotated inwards. Isolated club foot is an anomaly that entails all the tissue below the knee. A mutation in the PITX1 gene, which encodes the PITX1 protein results in heterozygotes that then causes the club foot anomaly. This represents how it plays a crucial role in developing lower limbs. Discovering how PITX1 can affect the development of lower limbs and can be a factor in the development of club foot proved how it can be a single gene mutation that leads to club foot. Defects in the PITX1 protein leads to less regulation of the genes that aid in the formation of the lower legs and feet in humans. This means that there could be deformation in the muscles, bones and tendons that are in the lower limbs.
The DNA binding properties of PITX1 can lead to further complications and diseases. It has been found that if the DNA PITX1 is binding to has altered or mutated in someway then this can lead to Liebenberg Syndrome. This syndrome leads to odd development of upper limbs and can lead to various deformities in the arm. Some cases are more severe than others, as in some situations it may lead to shorter fingers and in other situations it can lead to restriction on bending one’s elbow. There are multiple mutations of DNA that can lead to this, as it alters the binding of the PITX1 protein and then this leads to developmental issues. The mutations in the DNA alter the regulatory elements of the DNA and this will eventually end up with the PITX1 protein not being able to bind as much as it should. In Liebenberg’s syndrome the molecules that enhance certain genes are not working as they should and PITX1 would be binding more than it should. Or rather, it could lead to some other molecules that usually regulate the PITX1 protein to act and so it leads to PITX1 protein acting too much in the development of the hands and arms.4 In Liebenberg syndrome there are promoter groups that enter the PITX1 locus that should not typically be there or that have mutated.
Stickleback Fish
The effects of the PITX1 protein have been studied further within stickleback fish. The researchers studied two isolated populations of fish. They theorized how the PITX1 gene and how it encodes the protein acts a “regulatory switch”. However, defects in the switch can lead to defects in the development of the hind limbs. In marine stickleback fish they have a pelvis and a protective spine. But, in the freshwater populations of stickleback fish they physically show deformities in these body parts. The freshwater stickleback fish have a missing pelvis, or it is at least reduced and less prevalent. This has been found to be due to the PITX1 gene not properly encoding the PITX1 protein, which is ever so important in the development of the hind limbs of animals. Using the stickleback fish, researchers further identified how the PITX1 gene and protein are regulated differently depending on the tissue types in the animal. Therefore, the jaw tissue, pituitary tissue and the pelvic tissue are all regulated differently for PITX1. This is how it was found that the PITX1 for pelvic tissue has a regulatory switch in marine stickleback fish, but does not have a regulatory switch for pelvic tissue in freshwater stickleback fish. The reason for the lack of a pelvic regulatory switch in freshwater stickleback fish is due to the mutation or deletion that gets in the way of a pelvic promoter (Pel-beta) and its general function.
Structural highlights
The known structure of the PITX1 protein in humans is composed of three alpha helices and a beta sheet. It is a monomer, as it is composed of amino acids starting and finishing with arginine. Arginine is present at the carboxy-terminus and at the amino-terminus. The full structure has not been entirely found yet. The entire found structure is DNA binding. In experiments, the researchers will often create mutant versions of the protein by altering the . The N-terminus is where epitopes bind to the protein, thus making this part of the structure integral to the role of the overall protein. When researchers attempted to use mutants of the protein with the N-terminus deleted, the data collected was inconclusive as the epitopes usually bind to this site and therefore had nowhere to go in these trials. The C-terminal end of the protein is what gives it the ability to bind to SF-1 and other molecules in a sort of ligand-binding domain.3 There was also found to be a certain set of forty-nine amino acids within PITX1 that carries great influence on its activation, however this region has not been explicitly identified. The serin and proline motifs within the protein are essential in its activation as well along with a FACE region, which includes fourteen amino domains.
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