The Late Phase of HIV type 1 replication involves the assembly of Gag proteins with the plasma membrane of hematopoietic cells. The binding is enhanced by the matrix domain of Gag. The matrix domain is also involved in cleaving Gag into the matrix, capsid, and nucleoplasm particles. The assembly of Gag proteins and plasma membrane takes place at lipid rafts to form immature virions. However, Phosphotidylinoistol 4,5-biphosphate has been found to carry out the same role played by matrix. Pl(4,5)Pz can trigger myristyl switch. In addition to it enhancing membrane anchoring, it also plays a crucial role in suggesting appropriate ways for Gag to membrane rafts.
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Pl(4,5)P2 contains two long-chain fatty acids that play the role of promoting micelle formation. Cellular form of Pl(4,5)P2 also contains stearate at position 1 and arachidonate at position 2 of glycerol group. Substoichiometric addition of amounts of Pl(4,5)P2 species in myristoylated MA and myristoylated MA lead to stern broadening in the 1H-14N (HSQC) NMR spectra. It also led to the signals for NH groups to broaden beyond detection (Bhardwaj, 56).
Myristyl is very crucial in the replication process of Late phase HIV type 1, however, the mutation process can hamper with myristoylation process leading to inhibition of membrane binding in vitro. This can result in Gag targeting cytoplasm and other intercellular membranes instead of the plasma membrane. Occasionally, Gag molecules are known to assemble and bud from the plasma membrane via indirect routing (Bhardwaj, 81). On the other hand, in primary macrophages budding was found to be occurring in multivesicular bodies.
According to the research carried out, localization of Gag molecules in virus assembly depends on Pl(4,5)Pz. Pl(4,5)Pz also plays a significant role in marking membranes of specific cellular proteins. Depletion of Pl(4,5)Pz hampers virus assembly and results in piling of Gag molecules at membranes of late endosomes and MVBs (21). On the other hand, induction of Pl(4,5)Pz filled with endosomes redirects Gag into targeting endosomes or MVBs. Induction also stimulates intravesical budding. The replacement of MA with membrane-binding N end Fyn kinase results in a reduction of virus sensitivity in assembling to Pl(4,5)P2 that results in manipulation.
In the study of the structure of di-C4-Pl(4,5)P2:myrMA Complex, it was observed that myrMA was absent. The binding of di-c4-Pl(4,5)P2 was found to be because of the elimination of the myristyl group. Exposure of myristate was found to be induced by an allosteric mechanism. This was shown by the binding that took place between di-c4-Pl(4,5)P2 and myrMA (Bhardwaj, 77). The binding of di-c4-Pl(4,5)P2 and myrMA resulted in structural changes of more. From the structural changes observed on myrMA, it was deduced that myristate exposure was triggered by an allosteric mechanism. In the process, Pl(4,5)P2 binding stimulates slight significant changes in the beta-hairpin that is responsible for the observant changes in the orientation of the helical structure.
The specific binding of Phosphatidylinositide is enhanced by hydrophobic and electrostatic interactions. Its lipids facilitate intracellular interactions that enhance the identification of organelles. Various groups of proteins interact freely with the diverse groups of phosphatidylinositides with the aid of lipid molecules. The studies that have been carried out show that HIV-1 attacks and affects the phosphatidylinositides signal system hence proving that Pl(4,5)P2 plays a crucial role in enhancing the attachment of Gag to the PM.
Present studies also show that Pi(4,5)P2 can act as an allosteric trigger for myristate exposure. It also acts as a direct membrane anchor by providing mechanisms for attaching Gag to membranes enriched with Pl(4,5)P2.
Neurodegenerative diseases have been learned to be increasing with the aging of the population. However, their link with genomic mutation is too minute; this is because of the finding that mutation causes slow changes in neural functions. The majority of neurological disorders have been associated with environmental changes. However, scientists have managed to come up with pluripotent stem cells device to enable them to solve neurological problems experienced.
The study of pluripotency
The study of pluripotency has its origin from the study of cell biology and cloning in mammals. According to a pluripotency study, primitive embryonic cells from mammals such as mice and monkeys can be used in making whole organisms. However, the generation of animals to be used in the study of neurological diseases in humans has proved difficult. This is because of difficulties in matching the genetic composition of the models with the real organisms.
In addition, the majority of the animals used in the production of models lack some chromosomes present in human beings, for instance, the mouse lacks chromosome 21. To overcome the problem of animal model limitations, everlasting neural cells are used in the culturing of tissue models. However, the use of immortal cells also poses a challenge to the treatment of neurological disorders. For instance, in the use of immortal cells in the production of culture tissues, abnormal cells may be produced. In addition, the disease-expressing genes may be over-expressed.
According to the research carried out, the generation of iPS cells can aid in generating diverse neurons and neural support cells like those found in the brain and the spinal cord, hence enhancing the containing of neurological diseases. In addition, the development of iPS cell models will be of great advantage to both neurodegenerative and neurodevelopmental diseases. An example of neurodevelopmental disorder is fragile X syndrome.
Fragile X syndrome is an inheritable form of mental impairment. It is a result of the increase of the trinucleotide sequence. During the expansion of trinucleotides, there is a loss of FMR1 protein that results in developmental variations in the cerebral cortex (Sidhu, 67). Dendric cells in the region of the brain that contains extensive trinucleotides are immature in shape. The lost FMR1 gene is only observed in embryonic stages and silenced in adulthood.
X-chromosomes also portray some syndromes such as Rett’s syndrome. Rett’s syndrome is usually caused by impulsive mutations. Most of the people portraying this disorder are female; this is because Rett’s syndrome results in male fetuses’ death. The severity of Rett’s syndrome in women is evidenced by the specific changes in genes loci and inactivation of x-chromosome shapes.
iPS models will also be of great advantage in Down’s syndrome. Down’s syndrome is a result of the trisomy of chromosome 21. Through iPS, human fetal NPCs have been found to develop Down’s syndrome that can be used in the reprogramming process.
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Spinal muscular atrophy is also an example of an autosomal recessive disorder that causes infantile death. It is a result of the loss of SMN1. Patients suffering from spinal atrophy have been found to lose SMN protein, which results in cell demise and deterioration of muscles. Other diseases that can be managed by the implementation of iPS include Huntington’s disease, Parkinson’s disease, and Amyotrophic lateral sclerosis (Yildrim, 173).
Huntington’s disease is caused by the repetition of expanded CAG in exon 1 of HTT. The severity of this disease is expressed by the aggregation of proteins within the nucleus of certain neurons. Parkinson’s disease is depicted by the production of neurons that produce dopamine throughout the brain. On the other hand, Amyotrophic lateral sclerosis is an adult sporadic genetic disease that leads to paralysis and atrophy of muscles. Although iPS contributes immensely to the production of neurological models, it cannot manage to produce all cells of neurological lineages. Due to this, neurological diseases cannot be managed completely.
Bhardwai, Nitin. A Comprehensive Bioinformatics Study of the Interaction Between Peripheral Proteins and Membrane. Chicago:ProQuest, 2007. Print.
Sidhu, Kuldip. Frontiers in Pluripotent Stem Cells Research and Therapeutic Potentials. New York: Bentham Science Publishers, 2012. Print.
Yildirim, Sibel. Induced pluripotent stem cells. New York: Springer, 2012. Print.