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

August 9, 2010

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: bental@ashtoret.tau.ac.il

SOURCE Tel-Aviv University


Source: newswire



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