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From Proteopedia

Revision as of 02:44, 29 April 2011

RAS PROTEIN

INTRODUCTION

Human beings fear when they hear the term “cancer.” When a person is diagnosed as having cancer, such news is always devastating. So, what is cancer? It is a disease in which cells exhibit uncontrolled growth and invasion that intrudes and kills adjacent tissue, and for most cases, it is lethal. Documents regarding to cancer can date as far back as 460BC, and reports on patients having symptoms resembling that of cancer could be found throughout the history of mankind. Ancient Greek physician Hippocrates described multiple kinds of cancers and referred them as carcinos. Since its discovery approximately 2500 years ago, there still is not a definite cure for the deadly disease. However, throughout the past few decades, with improved technology, medical communities now have a better understanding in treating the disease, or perhaps, slowing the spread of malignant cells. We now know that the onset of cancer is tightly related to the mutation in ras gene. Being involved in 30% of human cancer, hyperactive Ras is currently being heavily investigated as a possible target for novel drugs. Rat Sarcoma protein, also known as Ras, is the functional product of ras gene. It belongs to the large super-family of proteins known as “low-molecular weight G-proteins.” They are referred to as G-proteins due to their abilities to bind to guanine nucleotides (GTP and GDP). Ras is most commonly known by its ability to conduct extracellular signal to inside the cell. Ras triggers and causes responses in more than 20 effectors and regulate processes such as proliferation, survival and differentiation in cells.

HISTORY

When first investigated by scientists, two ras genes, HRAS and KRAS were identified as being responsible for the cancer-causing activities of sarcoma viruses. These viruses were found in rat, hence the name Rat sarcoma. Further investigations identified another ras gene in human neuroblastoma cells, the genes were designated as NRAS.

CLASSIFICATION

Ras protein is a member of small GTPases, and it is distinguished from the heterotrimeric G-proteins, often known as the large G protein. While both G protein subfamilies are capable of signal transduction and binding to GTP and GDP, the two differ in that heterotrimeric G proteins are made up of multiple subunits: alpha, beta and gamma, whereas small GTPases are monomeric. In fact, the small GTPases are homologous to the alpha subunit of the heterotrimers.

STRUCTURE

contains 5 alpha helices and six-stranded beta sheet. The G domain that binds to the guanosine nucleotide, has 166 amino acids with mass around 20kDa. It has five motifs that directly bind to either GDP or GTP. The five motifs are designated from G1 to G5 respectively. P-loop of G1 binds to the beta phosphate of GDP and GTP. Threonine-35 of G2, aspartate-57 of G3, and alainine-146 of G5 all bind to GDP and GTP as well. Binding of magnesium ions facilitate nucleotide binding to Ras. As Ras switches from its inactive to active state, two switches are moved. The first switch includes threonine-35 and the second has a glycine-60 in DXXG motif. ^[1]