Creative Minds: Of Arsenic and Misfolded Proteins

Posted on October 29th, 2015 by Dr. Francis Collins

Taking out the trash is a must in every household. Inside our cells, it’s also essential because if defective proteins are not properly disposed of, they can accumulate and make a mess of the cell’s inner workings, leading to health problems.

John Hanna, a physician-scientist at Brigham and Women’s Hospital, Boston, is on a quest to study the cell’s trash disposal system in greater detail. In particular, this 2014 NIH Director’s Early Independence awardee wants to learn more about how cells identify proteins that need to be discarded, how such proteins are steered towards the molecular garbage can, and how, when the process breaks down, neurodegenerative conditions, cancers, and other diseases can arise.

That’s a complex challenge, so Hanna will start by zeroing in on one particular component of cellular waste management—the component that clears out proteins damaged by arsenic. Although arsenic is notorious for being the poison of choice in countless true crime shows and mystery novels, this semi-metallic element is found naturally in soil, water, air, and some foods.

Cells can detoxify low levels of arsenic, but can handle only so much before the stuff begins interacting with normal proteins, causing them to destabilize, unfold, and accumulate in toxic aggregates. To help keep this from happening, an important component of the cell’s waste-management system kicks in: a molecule called ubiquitin tags misfolded proteins, marking them for removal. Tagged proteins are then transported to amazing nanomachines called proteasomes, which are barrel-shaped structures located within the cell. There they are routed through an elaborate system of enzymes and other molecules to degrade and recycle their parts.

In 2014, Hanna and colleagues discovered two proteins involved specifically in transporting misfolded arsenic-bound proteins to the proteasome. The proteins, called Cuz1 and Tmc1, were identified in Saccharomyces cerevisiae, or budding yeast, which we use to make bread and beer. Though separated from humans by about 1 billion years of evolution, this species of yeast shares basic cellular properties with humans, providing a valuable laboratory model for finding new clues about how our cells work. In fact, a human protein related to Cuz1 already has been identified [1].

With his Early Independence Award, Hanna will use these two proteins to explore a key question in protein degradation: How does the cell’s waste-management system generate and maintain a dedicated response to remove misfolded, arsenic-laden proteins? What Hanna learns about this specificity can be applied to study other aspects of a cell’s trash-sorting system and how they might selectively dispose of other types of misfolded proteins, such as those formed by gene mutations or damaged by heat or age. Hanna’s hope is that a more detailed understanding of how cells destroy damaged proteins might allow us to design molecules that can activate specific degradation routes when needed.

For example, in previous studies Hanna and his colleagues, working in the lab of Daniel Finley at Harvard University, Cambridge, MA, identified a chemical compound that boosts the ability of proteasomes to destroy damaged proteins [2,3]. They went on to test this compound in human cells with high levels of the tau protein, which is involved in the hallmark tangles found in the brains of people with Alzheimer’s disease. In those test tube experiments, the compound significantly dropped levels of tau. The approach is so promising that Massachusetts-based biotech companies Proteostasis and Biogen have licensed the proteasome-boosting compound and are now exploring its therapeutic potential.

References:

[1] A conserved protein with AN1 zince finger and ubiquitin-like domains modulates Cdc48 (p97) function in the ubiquitin-proteasome pathway. Sá-Moura B, Funakoshi M, Tomko RJ Jr, Dohmen RJ, Wu Z, Peng J, Hochstrasser M. J Biol Chem 2013 Nov 22;288(47):33682-33696.

[2] Deubiquitinating enzyme Ubp6 functions noncatalytically to delay proteasomal degradation. Hanna J, Hathaway NA, Tone Y, Crosas B, Elsasser S, Kirkpatrick DS, Leggett DS, Gygi SP, King RW, Finley D. Cell. 2006 Oct 6;127(1):99-111.

[3] Enhancement of proteasome activity by a small-molecule inhibitor of USP14. Lee BH, Lee MJ, Park S, Oh DC, Elsasser S, Chen PC, Gartner C, Dimova N, Hanna J, Gygi SP, Wilson SM, King RW, Finley D. Nature. 2010 Sep 9;467(7312):179-84.

Links:

Arsenic (National Institute of Environmental Health Sciences/NIH)

Monster Mash: Protein Folding Gone Wrong (National Institute of General Medical Sciences/NIH)

Hanna Laboratory (Brigham and Women’s Hospital, Boston)

Hanna NIH Project Information (RePORTER/NIH)

NIH Director’s Early Independence Award Program

NIH Support: Common Fund