This is a model of the structure of clathrin, a protein that researchers at The University of Texas Health Science Center at San Antonio used to study how a heat shock protein disassembles protein complexes. Credit: Drs. Eileen Lafer and Rui Sousa/UT Health Science Center at San Antonio
Heat shock proteins ram into other proteins, generating force that is beneficial. Studies at The University of Texas Health Science Center 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.
Prof Rui Sousa, Ph.D. and Prof Eileen M. Lafer, Ph.D showed 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.
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. 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.
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. https://news.uthscsa.edu/microscopic-collisions-help-proteins-stay-healthy/
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