Ras Protein and Pancreas Cancer

Ras proteins are the founding members of a large superfamily of monomeric small GTPases. These proteins are best known for their ability to serve as molecular switches regulating diverse cellular processes that include cell cycle progression, cell survival, actin cytoskeletal organization, cell polarity and movement, and vesicular and nuclear transport ^[1]. Both unicellular and multicellular organisms express Ras proteins. The human Ras superfamily is divided into five major branches: Ras proteins, Rho, Ran, Rab, and “unclassified” sequences ^[1]. Even though these are separated branches, they share a lot of similarities not only in their structure but also in their functions.

Function

1CTQ has three functions, the first one is GDP and GTP binding which consist of the interaction in a non-covalent way with guanosine diphosphate and guanosine triphosphate. The second one involves the catalysis of GTP and water to give GDP and phosphate. The third one and not less important is the interaction to the end part of a polypeptide chain where the terminal group is carboxyl, and this carboxyl isn’t performing its function of attaching to an amino acid residue. It is an important molecule because it acts in signal transduction so that means that it is activated by a receptor and sends information from the inner part of the cell to the outer part. It coordinates the activities of different cells, however, if this one fails, sends wrong information it can be harmful and diseases can be present ^[2]. To get a better understanding of G proteins, we must know their function. G Proteins act as switches that regulate information in the cell, it can activate or deactivate. It acts as a signaling protein which sends information to the cell receptors to a variety of effectors. These proteins are all found in eukaryotic cells, and they control metabolic, humoral, neural, and developmental functions. More than a hundred different kinds of receptors and many different effectors have been described ^[3].

Disease

The absence of, or mutations of these proteins cause major diseases, cancers in lungs, bladder, pancreas, and heart are the most common but not the only ones. These proteins are very important for everything because they control a lot of functions in cells. The absence of, or mutations of these signaling proteins can cause terrible damage to our body. The gene KRas which produces the KRas protein, this protein participates in cellular signaling, it controls the growth and death of cells. The normal form of this protein is natural KRas but when it gets mutated, different types of cancer can be found such as lung, colorectal and pancreas. Having these changes (mutations) might have a possible stimulation in the cells’ growth causing this the spreading of the cells in the body. Is key to verify if the tumor has the shape of a mutated or natural KRas gene so that the treatment of the cancer can be planified. The RAS family of small GTPases includes three genes: HRAS, NRAS, and KRAS. Each RAS protein is comprised of two major domains, the G domain and the membrane targeting domain (Daniel ZeitouniOrcID, 2016). All of the isoforms are similar in the amino acid sequence of the G domain with major differences being restricted to the hypervariable region of their C-terminal domains. Mutations in RAS occur in residues 12, 13 and 61, and inhibit GTP hydrolysis activity (Daniel ZeitouniOrcID, 2016). The three RAS genes constitute the most frequently mutated oncogene family in human cancers; however, the specific isoform and amino acid mutation varies among cancers (Daniel ZeitouniOrcID, 2016). Mutations in HRAS are most frequently found in melanoma, bladder and mammary carcinoma; NRAS mutations are found in melanoma and thyroid carcinoma; and KRAS mutations are most prevalent in cancers of the bladder, ovary, thyroid, lung, colon and pancreas. In pancreatic cancer, mutations in codon 12 of KRAS occur the most frequently (Daniel ZeitouniOrcID, 2016). RAS proteins play an active role in cell differentiation, proliferation, migration, and apoptosis, making them important in cancer signaling (Daniel ZeitouniOrcID, 2016). Individual RAS proteins are activated when they are bound to guanosine triphosphate (GTP) and are inactive when they are bound to guanosine diphosphate (GDP). Intrinsic RAS GTP-GDP cycling is regulated by guanine nucleotide exchange factors (GEFs) that stimulate nucleotide exchange and by GTPase activating proteins (GAPs) that accelerate the intrinsic GTP hydrolysis activity of RAS (Daniel ZeitouniOrcID, 2016). Once activated, RAS-GTP preferentially interacts with a spectrum of catalytically diverse downstream effectors that then regulate a myriad of cytoplasmic signaling networks (Daniel ZeitouniOrcID, 2016). KRAS plays a vital role in PDAC and is believed to be a key target for treatment. Decades of research have shaped our understanding of the biochemistry, structure, and cellular signaling of KRAS in cancer. This foundation of knowledge can be viewed in two ways: support for the need to find different routes to silence KRAS, or fodder for the notion that KRAS is “undruggable” (Daniel ZeitouniOrcID, 2016). By undruggable, it means that there is no such drug yet invented that can inhibit KRAS mutation a 100%. However there are some ideas to approach an effective treatment for pancreatic ductal adenocarcinoma (PDAC), one of them is direct inhibition of Ras, it is the best approach so far and it consists of small molecules identified as direct binders that altered RAS function targeted the site on RAS involved in its recognition by the RAS-GEF, SOS1. SOS1 catalyzes the exchange of GDP to GTP, the rate-limiting step in RAS activation, and thus regulates RAS activity (Daniel ZeitouniOrcID, 2016). In recent studies, RNA interference has been used to suppress KRAS expression, this has been validated as therapeutic strategies in mouse models of cancer (Daniel ZeitouniOrcID, 2016).

Relevance

Proteins are structured with and , in this case, Ras proteins are made up of five alpha helices and 6 beta sheets. The diphosphate-binding loop G1 (also known as P-loop), with the consensus sequence, connects the β1 strand to the α1 helix and contacts the α- and βphosphates of the guanine nucleotide. The connection between the α1 helix and the β2 strand corresponds to G2 and contains a conserved (Thr35) involved in Mg2+coordination. The G3 domain, at the NH2 terminus of the , links the sites for binding Mg2+ and the γ-phosphate of GTP. The G4 domain that links the β5 strand and the α4 helix recognizes the guanine ring. The G5 loop, located between β6 and helix α5, reinforces the guanine base recognition site ^[1]. Ras proteins act as connectors which connect the interior of the cell with the cell surface ^[1]. The binding to GTP and GDP determines whether they are activated or not, they undergo a conserved mechanism: Ras functions require the participation of distinct regulatory proteins to control the GDP/GTP cycling rate ^[1]. Indeed, the extent and duration of Ras activation in cells depend on the interplay between a variety of negative and positive regulators of the Ras cycle ^[1].

Structural highlights

Is a G-protein which works as a signaling protein in humans. From the p21 Ras family, it has an A chain. It is attached by a protein-ligand binding to a magnesium ion and to (GNP).

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