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The Molecular Perspective: The src Oncogene

Correspondence: David S. Goodsell, Ph.D., Associate Professor, The Scripps Research Institute, Department of Molecular Biology, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. Telephone: 858-784-2839; Fax: 858-784-2860; e-mail: goodsell{at}scripps.edu www: http://www.scripps.edu/pub/goodsell

Ponder, for a moment, how unusual it is to be a multicellular organism. Human bodies are composed of ten trillion cells in several hundred varieties. Each cell produces its own energy, builds its own proteins, lives its own tiny life with its own microscopic goals. The only thing that holds us together is the dynamic web of communication between these cells, communication directly by touch and communication remotely through delivery of messages. When any of these messages are fouled, through mutation or by the deliberate commandeering of a rogue virus, the consequences can extend far beyond the life of the affected cell, even threatening the welfare of the entire body.

Oncogenes, in the large part, are sensitive links in our lines of communication. Corruption of these genes, and their products, causes fatal breaches in communication and cooperation between cells. These breaches may be errors in growth factors and cytokines that carry the messages from cell to cell. They may be errors in the receptors that receive the messages, blocking delivery or scrambling the meaning. Or, the fault may lie in enzymes, such as the Src protein, that relay messages inside cells.

Src was first discovered as a hyperactive form carried into cells by Rous sarcoma virus, which rapidly lead to transformation of the cell. The normal form was then found in healthy cells, where it sits at the center of a complex web of cellular communication, taking messages from a variety of cell-surface receptors and passing them on to proteins that control cell differentiation and proliferation.

Src is a biomolecular switch. Normally it is in an inactive state. But, when it finds an activated receptor on the cell surface, it switches "on." Then, it is an efficient protein tyrosine kinase, an enzyme that attaches phosphate groups to tyrosine amino acids in other proteins. The added phosphates, in turn, switch these proteins into the "on" state and they carry the message on to their ultimate targets throughout the cell, stimulating growth.

A clever combination of moving parts controls both the biological and chemical activity. The Src chain includes elements that bind to biological targets, and elements that mimic these targets. To recognize activated receptors, Src looks for polyproline helices with its SH3 domain and it looks for phosphorylated tyrosine residues with its SH2 domain. But most of the time, Src is held in an inactive form (Fig. 1), with its SH3 domain happily bound to an internal polyproline helix and its SH2 domain securely fastened to the phosphorylated tyrosine on its own tail. The rigidity of this structure, with the SH3 domain pressed tightly to the catalytic domain, firmly shuts the active site. With remarkable molecular parsimony, Src activity is blocked by the same structures that, once released, bind to receptors.

View larger version (68K): [in this window] [in a new window]   Figure 1. Architecture of Src. The Src protein is composed of a single chain that folds into several successive domains, as shown in this crystal structure of the human protein. The chain starts with a small anchoring domain, which is missing from this crystal structure, that affixes the protein to the interior face of the cell membrane. Next come two "src homology" domains, SH3 and SH2, so named because they are the defining feature of the class of regulatory proteins that form the "src family." The chain then forms an unusual polyproline helix, colored here in yellow, similar to the polyproline helices that are found in many receptors. Next in line is a large catalytic domain, split into a small half on the left and a large half on the right, with the active site formed in between. Finally, the protein ends in a short tail that contains the key tyrosine residue, shown in blue at the arrow, that is phosphorylated when the enzyme is inactive, as seen here. Coordinates were taken from entry 2src at the Protein Data Bank (http://www.pdb.org).

View larger version (58K): [in this window] [in a new window]   Figure 2. Action of Src. In spite of its simplicity, the Src protein has many moving parts. In the inactive form, on the left, the protein is held tightly in a ball. In the active form, on the right, the SH3 domain has released the polyproline helix and the SH2 domain has released the tail (now with a normal, unphosphorylated tyrosine), allowing the active site the freedom to open and gain access to the proteins that it phosphorylates. The active site binds ATP (in red), which provides the phosphate for the reaction. The first reaction will be to add a phosphate to the tyrosine (in blue) immediately adjacent to the ATP molecule. Once this site is phosphorylated, the enzyme will be fully active.

	ADDITIONAL READING

Top Additional Reading

 

• Brown MT, Cooper JA. Regulation, substrates and functions of src. Biochim Biophys Acta 1996;1287:121-149.
  
• Xu W, Doshi A, Lei M et al. Crystal structures of c-Src reveal features of its autoinhibitory mechanism. Mol Cell 1999;3:629 –638.
  
• Hubbard SR, Till JH. Protein tyrosine kinase structure and function. Annu Rev Biochem 2000; 69:373 –398.
  

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