Scialog: Collaborative Teams - 2017
Unraveling the Second Secret of Life: Are All Proteins Allosteric?
Allostery, one of the great puzzles of biochemistry, is the process by which molecules – either proteins or small-molecule drugs – can bind to enzymes at locations far from the enzyme active site yet still modulate activity. Despite the fact that allostery has been studied for half a century and has been accepted as a key phenomenon regulating activity within biological systems, the mechanisms by which a distant binding event can transmit signals through a protein remain unknown. Scientists are still asking themselves, is allostery a rare phenomenon, or is it common across all proteins in an organism but difficult to detect?
Understanding the prevalence of allostery and the mechanism behind it would have profound implications across multiple fields, from enzymology (understanding catalysis), to synthetic biology (designing enzymes with novel functions), to drug design (creating drugs that target particular members of highly conserved and medically important enzyme super-families), note researchers Polly Fordyce and Banu Ozkan.
Fordyce, Stanford University, and Ozkan, Arizona State University, recently won $112,500 in competitive funding enabling them to form a collaboration aimed at unravelling the puzzle and perhaps determining whether all proteins are allosteric.
Fordyce and Ozkan formed their collaboration at the most recent Scialog: Molecules Come to Life meeting, which was organized by the private foundation Research Corporation for Science Advancement (RCSA).
Scialog is a combination of “science” plus “dialog.” The unique conference encourages early career scientists to form multidisciplinary teams to identify and tackle critical research challenges. The program is designed to fund highly innovative, but untested, ideas with the potential for high impact on challenges of global significance.
The funding for Fordyce and Ozkan’s collaboration is provided by the Gordon and Betty Moore Foundation, which is cosponsoring Scialog: Molecules Come to Life.
The researchers already may be well on the way to solving the mystery of allostery because of the powerful tools they have developed. Ozkan’s research team has made advances in computer modeling that can identify potential allosteric sites – receptive sites on enzymes – and potential pathways by which these binding events may affect enzyme active sites. Meanwhile, Fordyce and her associates have made advances in methods for rapidly analyzing thousands of enzyme mutants to experimentally map and quantify connections within these pathways.
A major test of their combined techniques will be whether they can detect and measure allostery in an enzyme previously not know to be affected by the process. For that test they will be focusing on Glucocerebrosidase, an enzyme associated with Gaucher disease, a rare genetic disorder in humans that causes easy bleeding and bruising, excessive fatigue, anemia, weak bones and joint pain, among other symptoms.