The dimer structure of an important tumor-suppressing protein, phosphatase and tensin homolog (PTEN), the second most frequently mutated protein found in human cancer, has been established by an international group of researchers carrying out studies using the BioCAT beamline 18ID at the U.S. Department of Energy’s Advanced Photon Source (APS), an Office of Science user facility. Their findings provide new insights into how the protein regulates cell growth and how mutations in the gene that encodes the protein can lead to cancer. The study was published online in Structure, and appeared in the October 6, 2015 issue.
Phosphatase and tensin homolog is a known tumor suppressing protein that is encoded by the PTEN gene. When expressed normally, the protein acts as an enzyme at the cell membrane, instigating a complex biochemical reaction that regulates the cell cycle and prevents cells from growing or dividing in an unregulated fashion. Each cell in the body contains two copies of the PTEN gene, one inherited from each parent. When there is a mutation in one or both of the PTEN genes, it interferes with the protein’s enzymatic activity and, as a result inhibits its tumor suppressing ability.
Membrane-incorporated and membrane-associated proteins like PTEN make up one-third of all proteins in our body; many important functions in health and disease depend on their proper functioning. Despite PTEN’s importance in human physiology and disease, there is a critical lack of understanding of the complex mechanisms that govern its activity.
Recently, researchers at Harvard Medical School found that PTEN’s tumor suppressing activity becomes elevated when two copies of the protein bind together, forming a dimeric protein. PTEN dimerization may be the key to understanding an individual’s susceptibility for PTEN sensitive tumors
In order to reveal how dimerization improves PTEN’s ability to thwart tumor development, the researchers in this study, from Carnegie Mellon University, the National Institute of Standards and Technology, the Center for Synchrotron Radiation Research and Instrumentation, the Illinois Institute of Technology, Monash University, Harvard Medical School, the University of Massachusetts Medical School, and Worcester Polytechnic Institute needed to establish the protein’s dimeric structure. Normally, protein structure is identified using crystallography, but attempts to crystallize the PTEN dimer had failed.
So the team used a different technique called small-angle x-ray scattering (SAXS), which gains information about a protein’s structure by scattering x-rays through a solution containing the protein. This experimentation was carried out at the BioCAT 18-ID-D x-ray beamline at the Argonne APS. They then used computer modeling to establish the dimer’s structure.
They found that in the PTEN dimers, the C-terminal tails of the two proteins may bind the protein bodies in a cross-wise fashion, which makes them more stable. As a result, they can more efficiently interact with the cell membrane, regulate cell growth and suppress tumor formation.
Now that more is known about the structure of the PTEN dimer, researchers will be able to use molecular biology tools to investigate the atomic-scale mechanisms of tumor formation facilitated by PTEN mutations. The researchers also hope that their findings will offer up a new avenue for cancer therapeutics.
See: Frank Heinrich, Srinivas Chakravarthy, Hirsh Nanda, Antonella Papa, Pier Paolo Pandolfi, Alonzo H. Ross, Rakesh K. Harishchandra, Arne Gericke, and Mathias Lösche, “The PTEN Tumor Suppressor Forms Homodimers in Solution,” Structure (2015), Oct 6;23(10):1952-1957. DOI: 10.1016/j.str.2015.07.012
Adapted from the original Carnegie Mellon University press release which can be read here.
This research was supported by the Department of Commerce (MSE 70NANB11H8139 and 70NANB13H009), NIGMS (R01 GM101647), NINDS (R01 NS021716) and the NSF (CHEM 1216827). This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science user facility operated for the DOE Office of Science by Argonne National Laboratory under contract no. DE-AC02-06CH11357. Use of the BioCAT facility is supported by grant 9 P41 GM103622 from the National Institute of General Medical Sciences of the National Institutes of Health.”