Nav: Home

Microscopic collisions help proteins stay healthy

August 05, 2016

SAN ANTONIO, Texas, USA (Aug. 5, 2016) -- Studies at The University of Texas Health Science Center at San Antonio are providing basic new understanding about "heat shock proteins," also called "chaperone proteins." These proteins, first identified in cells subjected to heat, are very important under many stressful and non-stressful metabolic conditions. They maintain proper protein function and, importantly, prevent the inappropriate accumulation of damaged proteins. For example, accumulation of damaged proteins such as beta amyloid, tau and synuclein are thought to be very important in the development of diseases of the brain such as Alzheimer's disease and Parkinson's disease.

Aug. 1 in the journal Nature Structural & Molecular Biology, a Health Science Center research team led by Rui Sousa, Ph.D., and Eileen M. Lafer, Ph.D., both professors of biochemistry in the School of Medicine, presented data that show how heat shock proteins break apart protein complexes. They found that when heat shock proteins with molecular weight 70 (Hsp70s) are recruited to protein complexes, rather than simply binding to these complexes, the Hsp70s collide with them and generate a force that dissolves the complexes.

"No one knew how the heat shock proteins pull apart bad protein complexes," Dr. Sousa said. "At the molecular level, everything is moving, colliding and bumping, and smashing into other components of the cells. We found that the system moves Hsp70s to where they are needed. Once this occurs, collision pressures pull things apart."

Model system

Previous attempts to glean this information failed because the proteins studied were too heterogeneous--of too many different sizes, shapes and actions--to isolate the Hsp70 behavior.

The UT Health Science Center team studied clathrin, a protein that is uniform in size and shape and is important in making intracellular cages that transport other proteins. Previously clathrin was only available from animal specimens, making it very difficult to manipulate experimentally. Dr. Lafer made a technical breakthrough when she was able to grow clathrin in bacteria for the first time using recombinant DNA technology. The clathrin could then be genetically engineered for mechanistic studies.

Dr. Lafer grew clathrin "cages"--shaped like microscopic soccer balls--that provided the biological raw material for Dr. Sousa and the team to study the force that occurs with Hsp70 collisions. The clathrin model system could be manipulated to yield precise results.

A wrecking machine

Dr. Sousa gave this analogy of the study: The heat shock protein is like a worker with an ax who, when moved to a wood pile, begins swinging. The wood pile represents a protein complex. The scientists give the worker both thick trees and thin trees to swing at, and spindly wood and hard wood. They change the angle of the wood pile, and every other variable, to learn how this affects the chopping.

By making variants of clathrin with recombinant DNA technology, team members were able to manipulate this biological material in ways that allowed them to determine the mechanism by which it is taken apart by Hsp70.

"This work was a tour de force, requiring the convergence of exceptional biochemical and molecular genetic skills with a deep understanding of the principles of physical chemistry," said Bruce Nicholson, Ph.D., chair of the Department of Biochemistry at the Health Science Center. "Such insights into the most basic aspects of protein chemistry and cell biology are often, as in this case, driven by a curiosity to find out how the molecular machines that drive our bodies work. But from these basic pursuits of scientific curiosity will often stem great benefits to human health."

Hsp70 in disease

Understanding Hsp70 behavior may have relevance to human disease. By increasing Hsp70 function, scientists cured Huntington's, a neurodegenerative disease, in a fly model. Cancer is another interesting focus. Tumors rely on Hsp70s to survive, so lowering Hsp70 function is a topic in cancer research.

"This is an impressive study that not only improves our understanding of cellular biology, but could lead to therapeutic discoveries for neurodegenerative diseases," said Francisco González-Scarano, M.D., dean of the School of Medicine and executive vice president for medical affairs of the Health Science Center. "It is a tribute to scientists who ask hard questions and develop tools to answer them. My congratulations to the team."

"We attacked this problem because it was a really important question in cellular biology," Dr. Lafer said. "We didn't do it because we wanted to cure neurodegenerative disease or cancer. We know, however, that when we attack really important questions in science and biology, it ultimately leads to translational applications down the line."

"Sometimes as a scientist you just increase understanding of the way the world works," Dr. Sousa said. "This is something scientists have wanted to know."
-end-
News online

For current news from the UT Health Science Center San Antonio, please visit our online newsroom, like us on Facebook, follow us on Twitter. or view us on YouTube.

About the UT Health Science Center at San Antonio

The University of Texas Health Science Center at San Antonio, with missions of teaching, research and healing, is one of the country's leading health sciences universities. Its schools of medicine, nursing, dentistry, health professions and graduate biomedical sciences have produced 33,000 alumni who are advancing their fields throughout the world. With six campuses in San Antonio and Laredo, the university has a FY 16 revenue operating budget of $801.8 million and is the primary driver of its community's $30.6 billion biomedical and health care industry. For more information on the many ways "We make lives better®," visit http://www.uthscsa.edu.

University of Texas Health Science Center at San Antonio

Related Neurodegenerative Disease Articles:

Special issue of Future Medicinal Chemistry explores advances in neurodegenerative disease therapy
Future Medicinal Chemistry, a leading MEDLINE indexed journal for medicinal chemists, has published two Special Focus issues on Medicinal Chemistry Advances in Neurodegenerative Disease Therapy.
Neurodegenerative disease mechanism and potential drug identified
Two new, UC Davis-led studies of neurodegenerative diseases linked to mitochondrial defects offer hope for developing a new biomarker for research and diagnostics, and a drug for treating such diseases.
Biomarker test for ALS useful in diagnosing canine neurodegenerative disease
In 2009, Joan Coates, a veterinary neurologist, along with other researchers at the University of Missouri and the Broad Institute at MIT/Harvard, found a genetic link between degenerative myelopathy (DM) in dogs and amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease.
Common factor links neurodegenerative disease in young and old
Scientists at the Gladstone Institutes and the University of California, San Francisco (UCSF), identified a common mechanism in two forms of neurodegeneration that affect young adults or the elderly.
Doctoral student's research looks at cause of neurodegenerative disease
A Kansas State University student hopes her research on a currently untreatable and progressive neurodegenerative disease will one day lead to treatment options.
Turning off the protein tap -- A new clue to neurodegenerative disease
Disabling a part of brain cells that acts as a tap to regulate the flow of proteins has been shown to cause neurodegeneration, a new study from The University of Manchester has found.
Potential Alzheimer's medication shows promise in mouse model of neurodegenerative disease
This month in the JCI, work led by Andrew Tobin at the University of Leicester tested two drugs that specifically target the M1 muscarinic acetylcholine receptor in a mouse model of Alzheimer's disease and discovered that the treatments had promising effects on symptoms of cognitive decline.
Stanford patient is first infant to receive lifesaving drug for neurodegenerative disease
Four-year-old Zoe Harting is doing well after participating in a phase-2 clinical trial of the first drug for a deadly genetic disease, spinal muscular atrophy type 1.
Mutant prion protein could help reveal neurodegenerative disease mechanisms
For the first time, scientists have isolated a mutated prion protein that can multiply in the lab but not in living animals, according to a PLOS Pathogens study.
Toxic peptides disrupt membrane-less organelles in neurodegenerative disease
St. Jude Children's Research Hospital scientists reveal how toxic peptides that arise due to amyotrophic lateral sclerosis and frontotemporal dementia target the integrity of membrane-less organelles and trigger disease.

Related Neurodegenerative Disease Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Anthropomorphic
Do animals grieve? Do they have language or consciousness? For a long time, scientists resisted the urge to look for human qualities in animals. This hour, TED speakers explore how that is changing. Guests include biological anthropologist Barbara King, dolphin researcher Denise Herzing, primatologist Frans de Waal, and ecologist Carl Safina.
Now Playing: Science for the People

#532 A Class Conversation
This week we take a look at the sociology of class. What factors create and impact class? How do we try and study it? How does class play out differently in different countries like the US and the UK? How does it impact the political system? We talk with Daniel Laurison, Assistant Professor of Sociology at Swarthmore College and coauthor of the book "The Class Ceiling: Why it Pays to be Privileged", about class and its impacts on people and our systems.