Tel Aviv University Research on the Mechanism of Copper Transport Into Human Cells may Enhance Chemotherapy

TEL AVIV, Israel, August 9, 2010 /PRNewswire/ -- A new study conducted in the department of Biochemistry and Molecular Biology at Tel Aviv University (TAU) elucidates the way in which toxic, yet essential, copper ions enter human cells. As a chemotherapy drug presumably enters the cells in a similar manner, the results of this study pave the way for the development of improved chemotherapeutic drugs. The groundbreaking work was published in the leading American scientific journal PNAS (Proceedings of the National Academy of Sciences).

The researchers, Prof. Nir Ben-Tal, Maya Schushan and Yariv Barkan of TAU and Turkan Haliloglu of Bogazici University in Istanbul, created a computational model demonstrating the structure, motion and function of hCTR1 (Human Copper Transporter 1) - a protein found in the membrane of human cells, and responsible for transporting copper ions through the membrane. Their findings are of particular significance because hCTR1 also carries the active chemotherapeutic agent cisplatin into the cell.

hCTR1 is a critical link in a chain of proteins ensuring the proper transport of potentially toxic copper ions to various intra-cell enzymes, that need them in order to fulfill many crucial functions. Failure in copper transport may result in serious illnesses, such as hemophilia, anemia, diabetes and cardiac disorders. However, due to the inherent difficulty of investigating the 3D structure and motion of proteins located in the cell membrane, little was known previously about hCTR1, and the way it actually carries the copper ions and/or cisplatin molecules into the cell (Fig. 1, mesh).

Applying an evolution-based approach, Prof. Ben-Tal and his team found elements of the protein preserved in different animals, including humans, and used this information to create a conjectured high-resolution 3D model of hCTR1's molecular structure (Fig. 1, spirals). They then proceeded to calculate the protein's main modes of motion (Movie 1). Finally, based on these models of structure and motion, they were able to suggest a mechanism by which the protein transports the copper ions into the cell.

Apparently, hCTR1 lets the ions through one by one, keeping them under close control (Fig. 2). Careful ion selection and regulation are essential because copper ions are highly reactive, producing large quantities of potentially harmful free radicals. Since hCTR1 also transports cisplatin into human cells, the new insight into this critical protein's transport mechanism has significant implications for the understanding, and eventually also the improvement, of chemotherapy treatments for cancer patients.

Figure legends:

Fig. 1 (http://bental.tau.ac.il/maya/structure.tif). The low resolution structure of hCTR1 (shown as grey mesh) revealed a central pore implicated in ion translocation, but could not unravel the precise molecular details of the structure. The model predicted in this study is shown as ribbons and colored by evolutionary conservation according to the scale below, with spheres indicating the specific location of each residue. Disclosing the molecular details of the structure, the model predicts that evolutionarily conserved residues face the ion pathway or form close interactions between the different structural elements (ribbons), thus stabilizing the structural scaffold.

Fig. 2 (http://bental.tau.ac.il/maya/mechanism.tif). The suggested ion translocation mechanism was predicted on the basis of the hCTR1 structural model. The elements important for ion transport, located at the entrance to the central pore (gray stars), are responsible for selecting copper over all other ions and compounds. After a copper ion enters the selection filter, the entrance to the pore is blocked, so that no additional ions can enter at the same time. When - and only when - the ion has been released inside the cell, the cycle is repeated. This allows close regulation of the translocation of this essential yet highly toxic ion. The chemotherapeutic drug, cisplatin, may enter the cell using the same pathway.

Movie 1 (http://bental.tau.ac.il/maya/MovieS1.gif). An illustration of one of the main modes of motions predicted to mediate copper transport.

    Credits: Maya Schushan did all the artwork (the movie and two pictures).

    Contact:
    Prof. Nir Ben-Tal
    Tel: +(972-3)640-6709
    Email: [email protected]

SOURCE Tel-Aviv University