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Halting Translation of Cancer Promoting Proteins

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        Most cancer drugs are designed to halt cell growth, the hallmark of cancer, and one popular target is the pathway that controls the production of a cell’s thousands of proteins.


        A familiar initiation factor, eukaryotic initiation factor 3 subunit d (eIF3d), has been found to harbor an unfamiliar feature—a sort of hidden compartment. What’s more, the hidden compartment pops open to bind a subset of cancer-related messenger RNAs (mRNAs). If this hidden compartment could be jammed, it might be possible to halt translation of the growth-promoting proteins, which are especially important to cancer cells, while preserving the translation of other life-critical proteins.


        The hidden compartment was uncovered by scientists based at the University of California, Berkeley. It came as a surprise because it occurs in a protein complex, eIF3, that has been known and studied for nearly 50 years. No one suspected its undercover role in the cell. This may be because eIF3’s ability to control mRNA translation selectively is turned on only when it binds to the set of specialized mRNAs. Binding between eIF3 and these mRNAs opens up a pocket in eIF3 that then latches onto the end-cap of mRNA to trigger the translation process.

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        “To me, it’s like finding a secret lever that opens a hidden drawer in an old-time desk,” said Jamie Cate, Ph.D., a UC Berkeley professor of molecular and cell biology and of chemistry. “The desk has been around over one and half billion years and many have studied it for decades, but we figured out how to trigger the opening.”


        Dr. Cate led a study that focused on a protein that is part of the eIF3d complex that helps the complex bind to mRNA. The study (“eIF3d Is an mRNA Cap-Binding Protein That Is Required for Specialized Translation Initiation”), which appeared July 27 in Nature, could help explain why translation of many mRNAs that require eIF4E continues, even if eIF4E is inactivated.


        “Here we describe a cap-dependent pathway of translation initiation in human cells that relies on a previously unknown cap-binding activity of eIF3d, a subunit of the 800-kilodalton eIF3 complex,” wrote the authors of the Nature study. “A 1.4 Å crystal structure of the eIF3d cap-binding domain reveals unexpected homology to endonucleases involved in RNA turnover, and allows modelling of cap recognition by eIF3d.”


        Essentially, the study points to a secret lever that triggers translation of a special subset of mRNAs—perhaps only 500 out of some 10,000 mRNAs produced by a cell. The study adds a new wrinkle to a familiar insight, one that emerged more than 40 years ago, that a so-called initiation protein must bind to a chemical handle on the end of each mRNA to start it through the protein manufacturing plant, the ribosome. Until now, this initiation protein was thought to be eIF4E (eukaryotic initiation factor 4E) for all mRNAs.


        Earlier this year, Cate and colleagues discovered that for a certain specialized subset of mRNAs—most of which have been linked somehow to cancer—initiation is triggered by a different protein in eIF3. Before, that protein was thought to be just one of a dozen or so general initiation factors required for mRNA translation.


        Instead, they discovered that eIF3, an assembly of 13 separate proteins, binds to a unique tag found only on this special subset of mRNAs.


        “What we found is that another protein, hiding in plain sight for over four decades, can also bind the chemical handle on the end of mRNAs to promote translation,” noted Dr. Cate. “It’s a component of eIF3—a protein called eIF3d—which has never before been connected to binding the handle.”


        Subsequent X-ray crystallography of eIF3d revealed the structural rearrangements that must occur when eIF3 binds to the mRNA tag and which open up the secret compartment. The researchers plan further studies using cryoelectron microscopy to locate the actual trigger that opens the compartment.


    “Basically, we found the button that opens the secret door, but we don’t really know what the button looks like yet,” Dr. Cate noted.

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