Relationship Of The Ras Function As A GTPase Essay

Question:

Explain Relationship of the Ras function as a GTPase?

Answer:

Introduction

The ras p21 proteins belong to the family of the related polypeptides found in all the eukaryotic living organisms from yeast to human. Their exceptional developmental conservation recommends that they have the fundamental cell capacities, in spite of the fact that the specific role they play remains obscure. The mutations in particular amino acids and the overexpression of ordinary proteins have got connected to the changed proliferation as well as the differentiation and, especially, to neoplastic procedures. The mature ras p21 proteins happen to get situated on the internal side of the plasma layer (Rhodes, et al., 2013). Furthermore, their biochemical properties incorporate the binding and the exchange of the guanine nucleotides and the GTPase activity. The favored speculation for ras capacity is that these proteins exist in harmony between a dormant compliance (p21.GDP) and the active conformation (p21. GTP) in which they can interface with their up 'til now obscure cell target or targets. Likenesses in the cell area, structure, and the biochemistry with other regulatory (G) proteins propose that they assume a significant role in the transduction of the signals from the surface of the cell.

Molecular Description of the ras p21

Protein ras p21 genetic group does the coding for a gathering that gets firmly to 21kDa (kilo Daltons) proteins having an exceptional proclivity for the guanine nucleotide sequences. On the other hand, the cell proteins having the comparable chemical and biological properties, altogether called the G-proteins, incorporate the G proteins responsible for the regulation of the adenylate cyclase (Spandidos, 2013). Which further involves the regulation of the alpha subcategory of the transducin of the outer bar of the retina. The as of late recognized rho quality proteins, and maybe likewise the prolongation elements. The Guanine proteins consists of the parts within the cell flag transduction, the ras proteins have shared similarities with the cell function within the interceding cell proliferation control. Late advance in the process of cloning and the gene sequencing of the earlier mentioned qualities, the excessive production of the quality items in the Escherichia coli, the engineering of the protein (Inoue, et al., 2013). The detailed biochemical portrayal, also, the atomic structure which gets controlled through the high determination the X-beam crystallography, the duo has clarified within the incredible detail of the p21 protein structure including the capacity of the p21 ras proteins.

Structure of the Protein

The crystalline structure of the protein has a considerable high resolution, among the typical eukaryotic oncogene protein is the c-H-ras. The protein lacks an adaptable of the carboxyl group deposit uncovers p21 protein which comprises of the six beta strands of the protein sheet, further has the four alpha helices, and the nine interfacing circles. About four circles get included in associations with the already bound guanosine diphosphate sequence (Wittinghofer, 2014). The strand sequence which comprises the phosphates, the other strand has a ribose group and the remaining two consists of the bases of guanine. The vast majority of the changing proteins consists of just single amino acids that gets substituted one after another. The organic elements of the staying five circles and other uncovered districts are at present obscure. Be that as it may, one circle relates closely with the binding site for the single cloned counteracting agent and the transformations in the last area don't modify guanine nucleotide official or guanosine triphosphates movement however they do lessen the changing action of actuated proteins (Wittinghofer, et al., 2013).

Relationship of the Ras function as a GTPase

Ras p21 assumes an essential part in intracellular flag falls intervening signs from the receptor and the nonreceptor tyrosine kinase to catalyze the cytoplasmic or atomic rections. Mutant types of the Ras p21 contribute in a vital path to the change of an assortment of tumor cells, and in this manner, Ras p21 is named an oncogene. Ras p21, an individual from the G-protein family, motions by performing GTP/GDP nucleotide trade. This can be initiated or hindered by other effector proteins. The structure appeared here is of Ras p21 complexed with a GTP simple (GMPPnP) to imitate the initiated type of the protein (Wittinghofer, et al., 2013). Ras proteins happen to be proto-oncogenes that often get transformed in the human cancers during the process of mutations. They get encoded by the three universally expressed gene including HRAS, KRAS and NRAS. These proteins get the GTPases that capacity as the molecular switches controlling the pathways in charge of the cell proliferation and its survival. The Ras p21 protein assists in the transmission of the signs within the cells commonly referred to as the signal transduction in the cells. The activated Ras aids in the activation of the protein kinase role of the RAF Kinase enzyme (Zhang, et al., 2014). Furthermore, the activated Ras also do activate the serine or the threonine-selective protein kinases in the cell.an example of the serine or the tyrosine or the threonine enzyme is the MEK and the MAPK.

The p21 protein regularly gets regulation through the Guanine Nucleotide Exchange Factors (GEFs). The Guanine Nucleotide Exchange Factors helps to enhance the binding activity of the GTP and the role of the GTPase activity in the invigoration of the inherent GTP enzyme that regulates the movement of the protein (Ostrem, et al., 2013). The enzyme GTPase also helps in the turning on conformation and turning it off. The distorted Ras capacity is related to hyperproliferative formative issue and malignancy and in tumors is related to a solitary transformation regularly at codons 12, 13 or 61 (Dror, et al., 2015). Change at these monitored destinations favors GTP official and produces constitutive initiation of Ras. Imperatively, all Ras isoforms share succession character in the greater part of the locales in charge of GDP/GTP official, GTPase movement, and effector collaborations proposing useful repetition. Notwithstanding this, it has turned out to be progressively clear that Ras proteins show isoform-particular capacities. These utilitarian contrasts are no doubt connected with the novel C-terminal hypervariable area (HVR) in each isoform, which is thought to balance the Ras/layer cooperation to indicate particular confinements in organelles and flagging nanoclusters.

Binding Characteristics of Ras Protein

The ras p21 protein has got the carboxyl terminal domain which facilitates the binding property. Further, the ras [protein has the GTP Binding proteins that perform the critical function in the signaling and the conformation with its binding characteristics. The protein consists of the amino acid sequences. In its structure, three of the amino acids happen to be hydrophobic and always exposed on the surfaces of the protein (Kumar Srivastava, et al., 2016). The hydrophobic amino acids include the A121, A122 and the L171. The hydrophilic amino acids remain buried deep inside the protein. Besides, only two of the total amino acids have got charges, K16 and the D57 amino acids. The two charged amino acids occur deeply inside the protein. The non-charged amino acids remain on the protein surface. The K16 and the D57 amino acids actively participate in the GDP and the GTP binding through the formation of the hydrogen bonds. Although, in the two areas of the ras protein consisting of the amino acids 116-119 and from 145-147happens to be highly conserved in all the ras molecules and they get themselves involved in the binding to the purine base of the GDP (Stephen, et al., 2014). Hence, the hydrogen bonds get formed in between the N116 and the D119, and the S145 and the A146. The N116 plays a key role in the determination of the conformation of the site for the GDP binding.

In the instances in which the Ras protein p21 gets switched on as a result of the incoming cellular signals, the p21 protein would subsequently put on the other proteins, that at the end turns on the genes which get involved in the cell growth, its differentiation and the survival. Usually the mutations in the ras genes leads to the production of the permanently activated p21 proteins (Kumar, et al., 2015). Due to the permanent activation of the Ras proteins would lead to the unintentional and the overactive signaling within the cell, even in the cases where there are no incoming signals. Due to the incoming signals resulting to the cell growth and the division, the overactive Ras signaling results to the ultimate cause of cancer. The three common human genes include the HRas, KRas, and the NRas are the key cancer causative oncogenes in human beings.

Conclusion

The ras protein p21 belongs to the family of the polypeptides that got commonly found in all the eukaryotic organisms. The protein has a three-dimensional structure that has got folds. As any other protein, it comprises of amino acids which are either polar or non-polar. The amino acids play a significant role in the GDP and the GTP binding to their designated sites. The ras protein gets controlled by the GEfs which promotes the GDP dissociation and stimulates the GTP binding. The protein consists of the amino acid sequences. In its structure, three of the amino acids happen to be hydrophobic and always exposed on the surfaces of the protein. The hydrophobic amino acids include the A121, A122 and the L171. The hydrophilic amino acids remain buried deep inside the protein. In the protein structure, a carboxyl terminal exists which enables the GTP binding capacity. The protein has got the crystalline structure which has a resolution of about 2.7 A.

References

Dror, R.O., Mildorf, T.J., Hilger, D., Manglik, A., Borhani, D.W., Arlow, D.H., Philippsen, A., Villanueva, N., Yang, Z., Lerch, M.T. and Hubbell, W.L., 2015. Structural basis for nucleotide exchange in heterotrimeric G proteins. Science, 348(6241), pp.1361-1365.

Inoue, S., Hao, Z., Elia, A.J., Cescon, D., Zhou, L., Silvester, J., Snow, B., Harris, I.S., Sasaki, M., Li, W.Y. and Itsumi, M., 2013. Mule/Huwe1/Arf-BP1 suppresses Ras-driven tumorigenesis by preventing c-Myc/Miz1-mediated down-regulation of p21 and p15. Genes & development, 27(10), pp.1101-1114.

kumar Srivastava, V., Chandra, M., Saito-Nakano, Y., Nozaki, T. and Datta, S., 2016. Crystal structure analysis of wild type and fast hydrolyzing mutant of EhRabX3, a tandem ras superfamily GTPase from entamoeba histolytica. Journal of molecular biology, 428(1), pp.41-51.

Kumar, A., Najafzadeh, M., Jacob, B.K., Dhawan, A. and Anderson, D., 2015. Zinc oxide nanoparticles affect the expression of p53, Ras p21 and JNKs: an ex vivo/in vitro exposure study in respiratory disease patients. Mutagenesis, 30(2), pp.237-245.

Ostrem, J.M., Peters, U., Sos, M.L., Wells, J.A. and Shokat, K.M., 2013. K-Ras (G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature, 503(7477), pp.548-551.Rhodes, S., Skinner, R.H. and Paget, M.J., 2013. CHARACTERIZATION OF RAS PROTEINS PRODUCED AT HIGH LEVELS IN THE. ras Oncogenes, 170, p.141.

Spandidos, D. ed., 2013. Ras oncogenes (Vol. 170). Springer Science & Business Media.

Stephen, A.G., Esposito, D., Bagni, R.K. and McCormick, F., 2014. Dragging ras back in the ring. Cancer cell, 25(3), pp.272-281.

Wittinghofer, A., 2014. Ras Superfamily Small G Proteins: Biology and Mechanisms 2. Springer International Publishing.

Wittinghofer, F., Kabsch, W. and Pai, E.F., 2013. Ute Krengel, Ilme Schlichting, Axel Scheidig, Matthias Frech, Jacob John, Alfred Lautwein. The Superfamily of ras-Related Genes, 220, p.183.

Wittinghofer, F., Kabsch, W. and Pai, E.F., 2013. Ute Krengel, Ilme Schlichting, Axel Scheidig, Matthias Frech, Jacob John, Alfred Lautwein. The Superfamily of ras-Related Genes, 220, p.183.

Zhang, S.C., Nouri, K., Amin, E., Taha, M.S., Nakhaeizadeh, H., Nakhaei-Rad, S., Dvorsky, R. and Ahmadian, M.R., 2014. Classical Rho Proteins: Biochemistry of Molecular Switch Function and Regulation. In Ras Superfamily Small G Proteins: Biology and Mechanisms 1 (pp. 327-340). Springer Vienna.

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