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McArdle News

2018

Cellular and molecular biology graduate student Adhithi Rajagopalan, a student in the lab of Jing Zhang, PhD at the McArdle Laboratory for Cancer Research, recently presented at the American Association of Cancer Research’s annual conference in Chicago. Rajagopalan’s presentation was part of a scientific session focused on animal models of cancer. UW Carbone physician-scientist Fotis Asimakopoulos, MD, PhD, a collaborator of the Zhang lab, co-chaired the session.

Rajagopalan presented on a new mouse model of advanced multiple myeloma. Multiple myeloma is a cancer of plasma cells in the bone marrow, and represents 15 percent of all blood cancers. In the initial phases of the disease, patients are typically asymptomatic. By the time symptoms arise – including anemia, bone pain and kidney disease – patients are in the late stages. Advances in therapies have helped extend survival times by driving the disease into remission, though there is no cure for multiple myeloma.

“It’s important to have some model way to study this disease in the advanced stages,” Rajagopalan said. “Because currently, we don’t fully know what disease mechanisms exist in the later stages or how we can better treat patients.”

A mouse model of early-stage disease exists, but not the advanced disease. Rajagopalan and co-lead author Zhi Wen, a scientist in Zhang’s research group, bred mice from the existing myeloma model with mice that harbored a second mutation in the Ras gene. Ras mutations are found in 45 percent of all advanced myelomas, but rarely in early-stage disease, suggesting the mutation plays a role in driving the later stages.

"In these mice, we can recapitulate much of the human disease,” Rajagopalan said. “This model now serves as a platform to test existing and potential therapeutics for many advanced multiple myeloma patients.” 

Adhithi Rajagopalan was one of over 60 UW Carbone Cancer Center researchers who presented their work at the conference, with dozens more attending to learn about current advances in understanding and developing treatments for cancer.

This article was repurposed from an original piece at https://www.med.wisc.edu/news-and-events/2018/april/carbone-scientists-annual-research-conference/

Professor of Oncology Dr. Norman Drinkwater is currently serving as Interim Vice Chancellor for Research and Graduate Education at UW-Madison, replacing Dr. Marsha Mailick (School of Social Work) who is on temporary leave from her vice chancellor duties. Prior to the appointment, Drinkwater had been serving as Associate Vice Chancellor for Research in the Biological Sciences since 2015.

Previously, Dr. Drinkwater served as the chair of the Department of Oncology and director of the McArdle Laboratory from 1992 until 2008. He is an accomplished Badger alumnus, completing both his undergraduate and graduate studies at Wisconsin-Madison, graduating with a Ph.D. in Oncology in 1980. Following postdoctoral research at Michigan State, he returned to UW-Madison and the McArdle Laboratory as a faculty member.

Dr. Drinkwater cites UW’s unique culture as a research institution as a key reason he has been drawn back to the university at various steps of his education and career. He highlights the focus on training graduate students and the collaborative environment of the university as two primary factors contributing to the success of research at Wisconsin. 

“When you start to work on a new problem or move in a direction that you don’t know much about, you can almost be guaranteed that one of the world’s experts on the subject is on this campus. And all it takes is a phone call,” says Dr. Drinkwater. “What makes Wisconsin different is that everybody here is invested in each other’s success.”

In 2014, the leadership of the Graduate School at the University of Wisconsin-Madison was reorganized to maximize the potential for research being conducted on campus. Traditionally, the dean of the graduate school had also served as the vice chancellor for research. The creation of a separate office of the vice chancellor for research and graduate education provided the opportunity for dedicated personnel to focus their full efforts on fulfilling the university’s research mission.

“We now have a significant number of people who spend their full time thinking about the research enterprise on campus,” says Dr. Drinkwater. “This includes what sort of investments we need to make to grow and be successful, what areas of research are ripe for new investment, new directions the campus can take, and what areas of campus research need to be invested in so they can be rebuilt.”

Drinkwater joined the new office as an Interim Associate Vice Chancellor at the request of Vice Chancellor Mailick in 2014. Wanting to give back to the university, he valued the opportunity to bring lessons learned from his 16 years of leadership in at McArdle Laboratory to his new role. Following an open search, he was formally selected for the position in 2015. 

“I took the Associate Vice Chancellor position to try and make a contribution to the success of the campus,” says Dr. Drinkwater. “Within the McArdle Laboratory, there has always been a strong sense among the faculty that we are all in this together, and that we should all work to grow and improve our institution. That stuck with me after I finished serving as chair.”

“Dr. Drinkwater has been an important and valuable resource and mentor to me throughout my career; he always has thoughtful advice and experience relative to successfully navigating both local and national research issues,” says Dr. Howard Bailey, director of the UW Carbone Cancer Center.

Says UW School of Medicine and Public Health dean Dr. Robert Golden, “I am delighted that Norm will be serving as Interim Vice Chancellor for Research and Graduate Education. He brings the perspectives of an experienced scientist, successful department chair, and university leader to this vitally important role.”

By Simon Blaine-Sauer

We are pleased to announce that McArdle Laboratory alumnus Dr. Lynne Maquat has been awarded the 2018 Wiley Prize in Biomedical Sciences. This prestigious honor is awarded annually to one or more premiere scientists by the Wiley Foundation to “recognize and foster ongoing excellence in scientific achievement and discovery.” Dr. Maquat was awarded the prize for her work elucidating the mechanism of RNA nonsense-mediated decay, which is a key process by which cells eliminate defective transcripts which could give rise to toxic proteins. 

Dr. Maquat conducted her postdoctoral research in the McArdle Laboratory, where she trained with Dr. Jeff Ross (now Professor Emeritus of Oncology). Dr. Maquat is the J. Lowell Orbison Endowed Chair and Professor in the Department of Biochemistry and Biophysics at the University of Rochester School of Medicine and Dentistry.

Read more about Dr. Maquat’s award and research here.

Dr. Dusty Deming

McArdle Laboratory and Department of Medicine scientist Dusty Deming knew he wanted to be a physician ever since he was in grade school. Since then, his desire to positively impact the lives of patients as both a clinician and a researcher has been reinforced many times over.

During his first semester of medical school at the University of Wisconsin School of Medicine and Public Health, Deming began working in the lab of Kyle Holen, a gastrointestinal oncologist at the UW Carbone Cancer Center. Having worked in a basic science laboratory as an undergraduate at Marquette, he was already passionate about research, and was excited to continue his laboratory work as a medical student. 

Deming’s time under Dr. Holen also allowed him to interact with patients in the clinic who were coping with cancer. Working directly with patients and witnessing first-hand the benefits research could have on their lives solidified Deming’s interest in oncology and cemented his desire to make research a prominent focus of his practice. 

“From that experience alone, I knew that for the rest of my career I wanted to be both a clinician seeing patients directly and also a researcher trying to develop the next, newest, greatest treatment options patients with cancer,” Deming says. 

Today, Deming is an assistant professor of medicine at the UW Carbone Cancer Center, specializing in gastrointestinal cancers. His primary appointment is in the Department of Medicine, but he holds a zero percent appointment in the McArdle Laboratory (Department of Oncology). This joint appointment allows him to participate fully in research and training as a McArdle faculty member with his salary support coming from his work as a physician.

Deming describes three main focuses for his lab’s research: precision medicine, sensitivity testing, and immunotherapy. In precision medicine, a patient’s genome is analyzed, allowing a treatment plan to be designed which will be most effective for that patient. Sensitivity testing involves growing patients’ cancer cells in vitro to predict how well the patient’s tumor might respond to various treatments. Immunotherapy, a rapidly accelerating area of cancer research, focuses on harnessing the power of the body’s natural defense system to fight cancers.

Consistent across Deming’s clinical practice and research focuses is his commitment to a more individualized approach to medicine.

“A major reason why more personalized medicine is becoming a major focus is that we know a heck of a lot more about the biology of cancers today,” Deming says. “When you understand the biology of a particular cancer, you realize that not all cancers are created equally and that there are certain things in different cancers that we as physicians can take advantage of in different situations.” 

As both a physician and researcher, Deming emphasizes that the goal of all of his lab’s research is ultimately to benefit patients. His lab is translational and collaborative by nature, with a mix of medical and graduate students, residents and postdocs.

“The relationship between basic and clinical research is absolutely critical,” Deming says. “You can’t do good clinical research without solid translational research, and you can’t do solid translational research without great foundational research.” 

The collaborative and transdisciplinary nature of research at the University of Wisconsin is one of the primary reasons Deming has remained here throughout the different stages of his education and career. One of his many current projects involves working with Dr. Melissa Skala, an investigator for the Morgridge Institute for Research and UW Carbone Cancer Center, to apply fluorescence imaging technology towards improving cancer treatments. Together, they are working on using optical fluorescence imaging to track the viability of cancer cells in response to different treatments and the sensitivity of cancer cells to various drugs.

Beyond his clinical interactions, Dr. Deming has an even more personal connection to colorectal cancer. In an ironic twist of fate, he was diagnosed with colon cancer himself several years ago. Although his own diagnosis did not alter his lab’s focus, it did underscore the urgency of his research for helping to improve the lives of cancer patients.

Looking ahead, Deming is optimistic about the future of cancer research, and sees tremendous promise in a wide array of research areas.

“My lab will tell you that I’m excited about everything, almost to an annoying level. With the ability to interact with great collaborators at McArdle and across the UW, and by working together in a team science format, we are going to make big strides and we are going to make them fast.”

By Simon Blaine-Sauer (blainesauer@wisc.edu)

Image on home page: Dr. Deming, second from right, with members of his laboratory group.

Night of HopeMcArdle Laboratory Director Dr. Paul Lambert (left) and UW School of Medicine and Public Health Dean Dr. Robert Golden (right) speak at the Night of Hope event.

On January 19th, McArdle students, staff, and faculty gathered together with teachers, staff, and supporters from Verona Area High School at Gray’s Tied House for the 13th Annual “Night of Hope” fundraiser. Festivities included a silent auction and raffles, with live performances by MUD Music and The Fauxtons. The annual fundraiser, which has grown steadily since its inception in 2005, raises money to benefit basic cancer research at the McArdle Laboratory (Department of Oncology). Additionally, Gray’s generously donates a portion of all food and drink sales made during the event.

The “Night of Hope” was inspired by the life of Verona Area High School teacher Anne Boehm. Ms. Boehm was a beloved member of the Verona community and a mother of three who passed away from breast cancer in 2006. The first “Night of Hope” was held to raise money towards supporting Ms. Boehm’s medical expenses and to allow her and her family to take a vacation.

In subsequent years, as more members of the Verona Area High School community were affected by cancer, the teachers of Verona decided to continue holding the event, and to donate the money to fund new cancer research. 

“The teachers of Verona wanted to raise money for a cancer institution where they could assure that 100% of the money was going to research, and they wanted to keep the money local,” said Nancy Cahill, who helps coordinate the event.

Over the years, the relationship between the McArdle Lab and the Verona Area High School staff has grown strong. McArdle faculty and staff have hosted several tours of their facilities for members of the Verona Area High School community, allowing them to meet with researchers and see the work that their generosity makes possible. Every year, McArdle faculty and staff look forward to participating in the festivities at Gray’s Tied House.

To date, the “Night of Hope” event has raised over $35,000 for research at McArdle and shows no signs of slowing down. This year’s event boasted one of the strongest showings yet by both Verona and McArdle staff, raising over $5,000.

The McArdle Laboratory wishes to thank the Verona Area High School staff, the amazing bands who performed, all who donated gift baskets and raffle items, and Gray’s Tied House for hosting. Your generosity and efforts make the cancer research breakthroughs at McArdle possible!

Coming up: On July 14, Nancy Cahill will host her annual Be The Cure event, to benefit the UW Carbone Cancer Center. More information on that event can be found here.  

This spring, the University of Wisconsin is offering a new course for graduate students within the Cancer Biology Training Program and other biology graduate programs to effectively apply bioinformatics approaches to their research.

The course, “Bioinformatics for Biologists”, is being team-taught by Eric Johannsen, M.D. and Mitchell Hayes. Dr. Johannsen is a faculty member at McArdle, a professor of medicine and oncology, and works within the UW Health Infectious Disease Clinic and as a member of the UW Carbone Cancer Center’s virology program. Mitchell Hayes is a Senior Research Specialist who has worked in the lab of Dr. Bill Sugden for several years.

Although other bioinformatics and information technology classes exist on campus, this new course aims to provide graduate students in the biological sciences with a more applied curriculum and more hands-on experience to maximally benefit their current and future research. Rapid advancements in the field of bioinformatics are continually unlocking new possibilities for breakthroughs and discoveries in the biological sciences. “Bioinformatics for Biologists” hopes to teach its students how to effectively utilize existing technology and challenge them to seek out areas in their research where novel technologies could be applied.

Contact Eric Johannsen (ejohannsen@medicine.wisc.edu) for more details.

Image on home page courtesy of https://www.publicdomainpictures.net

A stone dedicated by Blobel to his mentor Van Potter outside the McArdle Laboratory Building (1400 University Ave)

The McArdle Laboratory mourns the loss of Günter Blobel, Nobel Prize-winning cell biologist who discovered and characterized how proteins are targeted within cells. Blobel was one of the most successful graduates of UW-Madison’s long-running Cancer Biology Graduate Training Program, started in the McArdle Laboratory in 1952 as the first program in the United States to offer a Ph.D. in basic cancer research. Blobel received his Ph.D. in 1967, after training with Dr. Van Rensselaer Potter. He went on to doing groundbreaking research for five remarkable decades at the Rockefeller University in New York.

Blobel arrived at the McArdle Laboratory in 1964, having already received his M.D. from the University of Tübingen in Germany in 1960. At the time, Blobel’s brother was also studying at the University of Wisconsin, focusing on veterinary medicine.

In the Potter laboratory, Blobel studied how polysomes, groups of ribosomes that translate mRNA molecules into proteins, were localized within cells and how they attached to cellular membranes. Enthusiastic and communicative by nature, Blobel took full advantage of the resources available to him at the University of Wisconsin for interdisciplinary research, working with various other labs and departments on campus. For example, one of the groundbreaking papers included in his thesis represented a fruitful collaboration formed between Blobel and University of Wisconsin zoologist Hans Ris, who together used electron microscopy techniques to visualize polysome distribution patterns in rat liver cells.

In addition to his laboratory research, Blobel was also inspired by his mentor’s worldview and passion for education and outreach. Potter was a pioneer in the field of bioethics and emphasized the importance of humanity and beauty in approaching science. Blobel identified with this perspective and was highly committed to bettering the world both inside and outside of the lab. For example, both Blobel and Potter also shared a love of architecture. Potter actively supported Frank Lloyd Wright’s early proposal for Monana Terrace, while Blobel donated the entirety of his Nobel Prize winnings to the Friends of Dresden, a nonprofit he founded to rebuild and restore key parts of the city’s historic architecture destroyed during World War II.

“Günter was a free thinker, and the ideas he developed were new and original,” said Dr. William Dove, now Professor Emeritus of Oncology but a relatively new McArdle faculty member during Blobel’s time at Wisconsin. “In the early 70’s, how proteins are localized within cells wasn’t a hot topic of discussion; many scientists were more focused on elucidating the genetic code and regulating gene expression. How the parts of the cell were assembled and organized was a new area that Günter led molecular biologists to explore.”

After leaving Wisconsin for Rockefeller, the research Blobel conducted in Potter’s lab laid the foundation for decades of groundbreaking work in protein targeting. Blobel’s dedicated work ethic and creative approach to science guided him throughout a highly celebrated career.

“Even towards the end of his career, when I talked to Günter he would always have a new idea of his own,” says Dove. “He was always a free thinker and knew that to be a good scientist you have to prepare to be wrong.”

Read more about Dr. Blobel's amazing life and contributions to science here.

Paul Ahlquist and Masaki Nishikiori

Scientists at the Morgridge Institute for Research have discovered a promising new target to fight a class of viruses responsible for health threats such as Zika, polio, dengue, SARS and hepatitis C.

Masaki Nishikiori, a researcher in the Morgridge Institute virology group led by Paul Ahlquist, Morgridge investigator and professor of oncology and molecular virology at the University of Wisconsin–Madison, showed for the first time that, in replicating their genomes, viruses create pores inside parts of the cell that are normally walled off. This process of “punching through cellular walls” allows the virus to operate across different parts of the cell to activate and regulate its replication.

This could be big news in the quest to develop broad-spectrum antivirals, which are vaccines or drugs that target entire families of viruses. There are hundreds of viruses that threaten human health, but today the only way to combat them is by targeting each individual strain, rather than finding a common weakness.

The study, published on January 24 in the journal Science Advances, looks at a class known as positive-strand RNA viruses, which make up one-third of all known viruses (including the common cold). It appears that this pore-creating mechanism could be common across many or most members of this family of viruses.

“One exciting aspect of these results is that pores of different kinds in membranes are very important for many biological processes, and there are established drugs that interfere with them,” says Nishikiori. “We now recognize that this virus, and based on conserved features likely most viruses in this class, depend on similar types of pores to replicate. This is a target we know how to interfere with.”

Current pore-blocking drugs, also referred to as channel blockers, are used in treating high blood pressure, certain neurological or psychiatric disorders, including Alzheimer’s disease, and other maladies.

Nishikiori used biochemical and molecular genetic approaches to reveal the virus’ capacity to create and employ pores in a cell membrane. He used an advanced bromovirus model that allowed virus replication in yeast cells, which provided a highly controllable system to modify and assess both virus and host cell contributions.

In order to spread throughout the body, viruses hijack normal cell structures and functions to achieve their own ends. This class of virus, for example, always anchors its genome replication process to the membrane surfaces of cell sub-compartments or organelles (in this case, the endoplasmic reticulum). It had been understood this process occurred solely on one side of the membrane, outside of the organelle.

This study reveals the conventional view is incomplete. Nishikiori found that an enzyme called ERO1, which resides exclusively inside the organelle, on the opposite side of the membrane, is crucial to promoting the viral replication process. Reduce ERO1 and viral replication goes down, and vice versa, Nishikiori says.

The surprise was: How could an enzyme that was walled off from the virus by a solid membrane barrier activate viral growth? This was their first clue that something must be bridging the membrane. When combined with other insights, the team discovered that a key viral protein builds a pore or pipeline across the membrane, enabling ERO1 to affect viral replication on the other side.

Nishikiori previously found that the proteins creating these pores become strongly linked together by a particular kind of chemical bond, called a disulfide bond. However, these bonds can only be created in an oxidized environment. This explains at least one purpose behind the pores, Nishikiori says. They allow delivery of oxidizing power into the normally non-oxidized cytoplasm to form the disulfide bonds. “When the viral protein creates this pore, it allows oxidants generated by ERO1 to leach from the organelle interior into the cytoplasm and create a plume of oxidizing power,” he says.

Ahlquist speculates that the virus may use these strong linkages to keep the viral genome replication apparatus intact.  Drawing on other recent findings, he says viral replication complexes inside cells are under significant pressure and at risk of breaking off before replication is complete. The strong bonds might be similar to the wire cage holding the cork in place on a champagne bottle, he says.

Basic research on the mechanisms of viral replication is essential to the larger quest to find broad-spectrum antivirals, one of the holy grails of virology, Ahlquist says.

“When you apply an over-the-counter anti-bacterial cream to a child’s scraped knee, it works even though you don’t know exactly which bacteria you’re fighting,” he says. “We don’t have anything like that for viruses; most of our antiviral vaccines and drugs are virus-specific. We need new approaches that target broadly conserved viral features to simultaneously inhibit many viruses.”

Paul Ahlquist is the John and Jeanne Rowe Chair of Virology and director of virology, Morgridge Institute for Research. Ahlquist also is a professor of oncology and molecular virology at the University of Wisconsin–Madison and a Howard Hughes Medical Institute (HHMI) investigator.

This article was originally published at news.wisc.edu/an-achilles-heel-discovered-in-viruses-could-fuel-new-antiviral-approaches/

Left: a papillomavirus. Right: dioxins, polycyclic aromatic hydrocarbons (AHRs), and polychlorinated biphenyls (PCBs). PAS proteins regulate a variety of downstream responses to these three molecules, some of which are toxic effects.

McArdle is pleased to announce that Paul Lambert and Chris Bradfield recently received Outstanding Investigator (R35) Awards from the National Institutes of Health. The R35 award is designed to support proven research investigators, allowing them the flexibility to pursue projects with more ambitious scopes and potential for innovation. Lambert and Bradfield’s recent grants were awarded by the National Cancer Institute (NCI) and the National Institute of Environmental Health Sciences (NIEHS), respectively. 

Dr. Lambert is the director of the McArdle Laboratory, as well as the Howard M. Temin Professor and Chair of Oncology and the UW Carbone Cancer Center's Virology Program Leader. His grant was awarded in 2017 and provides 7 years of >$900,000 annual funding.

The research conducted under Dr. Lambert's grant will focus on the study of HPV-associated cancers, including anal, cervical, and head/neck cancers. High-risk strains of HPV are implicated in five percent of all human cancers, and HIV-infected persons have a significantly increased risk of developing these cancers. By using genetically engineered mouse (GEM) models, patient derived xenografts (PDXs), and a mouse papillomavirus model (MmuPV1) the Lambert lab will work to identify potential targets for the prevention and treatment of HPV-associated cancers. 

Dr. Bradfield is Professor of Oncology, director of the Molecular and Environmental Toxicology Graduate Program, a member of the UW Carbone Cancer Center's Genetics Program, and served as interim director of the Wisconsin Institute for Discovery (WID) from 2015 to 2017. His grant, also awarded in 2017, provides 8 years of funding of >$800,000 annually.

Bradfield’s R35 will allow him to undertake a collaborative and transdisciplinary approach to investigating the role of the PAS family of sensor proteins and how they interact with environmental factors to cause disease. PAS proteins are involved in sensing a variety of key physiological conditions, including oxygen status, microbiome changes, and circadian time. By investigating the pathways by which key PAS proteins act, the Bradfield group hopes to generate better prevention and treatment solutions for a wide variety of environmentally influenced conditions including epithelial hyperplasia, immunosuppression, teratogenesis, and tumor promotion.

We are also pleased to announce that additional R35 grants were recently awarded to several McArdle alumni including John Coffin, an American Cancer Society Professor of Molecular Biology at Tufts University; Elsa Flores, a Senior Member of the Moffitt Cancer Center; Thomas Kensler, Professor of Pharmacology and Chemical Biology at the University of Pittsburgh; and Gary Perdew, the John T. and Paige S. Smith Professor in Agricultural Sciences at Pennsylvania State University.

Congratulations to all McArdle R35 recipients, past and present! 

 

Note: The original version of this article failed to include Gary Perdew as a McArdle alumni recipient of an R35 award. We apologize for mistake.

Dr. Yongna Xing with lead author Cheng-Guo Wu

A new study by University of Wisconsin–Madison researchers identified the structural basis for how tightly bound protein complexes are broken apart to become inactivated. The structure explains why the complexes are less active in some cancers and neurodegenerative diseases, and offers a starting point to identify drug targets to reactivate it.

As we grow, our cells respond to tightly regulated cues that tell them to grow and divide until they need to develop into specialized tissues and organs. Most adult cells are specialized, and they correctly respond to cues that tell them to stop growing. Cancers can develop when something goes awry with those cues.

One such “stop and specialize” cue is found with the protein complexes known as PP2A. There are approximately 100 known PP2A complexes, and together they are estimated to regulate nearly one-third of all cellular proteins. These complexes consist of a core that is inactive until it mixes and matches with one of several specificity proteins to form tightly bound, active PP2A complexes. Active PP2A uses those specificity partners to find its targets – typically pro-growth proteins – and inactivates them. PP2A is a critical cue, then, in keeping cell growth in check and maintaining normal neurological functions. Not surprisingly, it is mutated in many cancers and neurological disorders.

“We know a lot about how active PP2A complexes form and are identifying more and more of their targets in cells, but we know very little about how they are inactivated,” explains Yongna Xing, an associate professor of oncology with the UW Carbone Cancer Center and McArdle Laboratory for Cancer Research and the senior author of a new study published on Dec. 22, 2017 in Nature Communications. “It’s a very tightly held complex, it’s almost like a rock, but there has to be a way to break it up.”

Xing’s previous work showed that PP2A is inactive when a regulatory protein, a4, is attached. However, when active PP2A complexes were challenged with a4, they remained active, meaning there had to be another trigger that broke the complex apart.

In the new study, Xing and her colleagues identify that trigger as the protein TIPRL. When they challenged active PP2A complexes with a4 and TIPRL, the complexes broke apart. Next, they determined the three-dimensional structure of TIRPL with PP2A through a technique known as X-ray crystallography.

“The structure shows how TIPRL can attack active PP2A complexes even though it has a much lower affinity than the specificity subunits do for PP2A core,” Xing says. “With the structure we were able to identify how TIRPL can attack the complex, change its conformation and, together with a4, make it fall apart robustly. It was hard to picture how this process could happen without structural insights.”

If we think of PP2A as a power screwdriver, the findings make a lot of practical sense. The core protein is the motorized base, and the specificity proteins – the ones that mix and match to help PP2A find the right target – are the screw heads. When you want to switch from a Phillips-head to a flathead screwdriver, you don’t throw away the whole power screwdriver complex and buy a new one; rather you detach one screw head and attach another. Similarly, it is energy costly for a cell to degrade the entire PP2A complex, so TIPRL’s role is to detach the specificity protein and recycle PP2A core.

One of the more interesting findings from the structure was how flexible TIRPL is compared to the specificity subunits, prompting the researchers to ask how PP2A mutations commonly seen in cancer patients affect TIPRL binding. Using either normal or PP2A core containing these mutations, they measured how well TIPRL and the specificity subunits can bind to it. They found that the core mutations have almost no effect on TIPRL binding, but they drastically weaken the binding of specificity proteins. These mutations, then, likely cause a shift from active PP2A complexes to the disassembled and inactive form.

“In many diseases, including cancers and neurodegenerative diseases, PP2A in general is less active, often due to mutations,” Xing notes. “This structure helps explain how those mutations lead to downregulation of PP2A by shifting the balance toward TIPRL-induced complex dissociation.”

With the structure in hand, Xing expects to be able to better understand the cycle of PP2A activation and inactivation, and how it regulates cell growth.

“For example, active PP2A is known to inhibit K-ras, a protein that drives growth in many tumors and currently has no good clinical inhibitors,” Xing says. “If you can find a way to re-activate PP2A, it could be very important in treating those cancers.”

The study was supported by National Institutes of Health grant R01 GM096060-01.

Slideshow image on home page: Structure of the PP2A-TIPRL complex, including the PP2A scaffold subunit (green), the PP2A catalytic subunit (blue), and the TIPRL (magenta). From Wu et al., Nature Communications 2017 Dec 22; 8(2272).

This article was originally published at https://news.wisc.edu/breaking-up-protein-complexes-is-hard-to-do-but-new-uw-study-shows-how/ 

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