Inositol Signaling Group
Stephen B. Shears, Ph.D.
Individual cells of the body have specific functions, such as to release or accumulate nutrient, to secrete salt and fluid, to contract, or to transmit an electrical signal. These specific events are co-ordinated and matched to the body's needs through changes in the levels of intracellular signals which control key molecular events within each of the cells. There are many opportunities for the environment to impact negatively upon intracellular signals and thereby perturb normal cell function. For example, there are biological agents (viruses and bacteria) and non-biological factors, such as toxins, UV radiation, or a thermal challenge, all of which can induce environmental “stress”. Understanding the normal operation of signaling systems helps us comprehend how they are perturbed by these environmental insults, and thereby offer us clues to improving human health through molecular intervention in these signaling pathways.
Phosphates are a recurring theme in the signaling field because of their ability to provide specificity to a molecule’s interactions with other cellular entities. For example, the bulky nature of the phosphate group establishes signaling specificity by imposing geometric constraints on ligand-protein and protein/protein interactions; a polyphosphate will only interact with its target when the phosphate groups are present in an appropriate three-dimensional array. Additionally, the phosphate’s negative charge at physiological pH is attracted to positively charged targets. Here, specificity comes from the participation of multiple ionic and hydrogen bonds.
Inositol polyphosphates (InsP5, InsP6 and their metabolites) represent a highly-specialized example of the recruitment of multiple phosphates. As many as eight phosphates are crammed into the relatively small volume surrounding a simple six-carbon, cyclic carbohydrate: inositol. These molecules have unique physico-chemical properties that require a high degree of technological specialization in order to accurately study their synthesis, metabolism and functions. The Inositol Signaling Group has a particular strength in this area that has enabled us to make a number of important conceptual advances.
For example, one especially notable feature of inositol is the plane of symmetry across the “head-to-tail” axis of this molecule. Thus, when the orientation of the inositol ring changes in relation to a protein’s ligand-binding site, one inositol phosphate can imitate another’s three-dimensional phosphate recognition pattern. This is an inherently promiscuous characteristic, yet we have discovered situations in which this underpins the action of specific inositol-based signaling cascades.
There is also the feature that the presence of so many phosphates in a confined space sometimes permits non-specific “delocalized electrostatics” to become powerful enough to over-ride the constraints of a geometric recognition pattern. One of the biggest challenges to the field is to distinguish biologically relevant "delocalized electrostatics" from experimental artifacts (such as those that might arise from the use of non-physiological levels of positively charged cellular constituents).
Our laboratory takes a multidisciplinary approach, utilizing techniques from the fields of biochemistry, molecular biology, confocal and FRET microscopy, flow cytometry, surface plasmon resonance, HPLC, structural biology, and electrophysiology. This helps us extend our understanding of the roles of inositolphosphates in many different aspects of human biology. This multidisciplinary environment also offers post-doctoral trainees many opportunities to expand their expertise.
Major areas of research:
- Study of the contributions that inositol pyrophosphates (InsP7 and InsP8) make in regulating cellular responses to a range of stressful situations, both extrinsic (environmental) and intrinsic (osmotic and metabolic).
- Study of the regulation by InsP4 of the conductance of a group of chloride-conducting ion channels in the plasma membrane, and in endosomes, and the impact of this regulatory process in cell biology.
Stephen B. Shears, Ph.D., received his Ph.D. in 1979 from the University of York in the U.K. He has published over 150 peer-reviewed articles in leading biomedical journals.