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SPRY Domain-containing SOCS Box (SSB) Protein Interaction With Par-4: Structure And Biochemical Implications
Funder
National Health and Medical Research Council
Funding Amount
$529,565.00
Summary
The suppressor of cytokine signalling (SOCS) proteins, are intracellular molecules that negatively regulate hormone and growth factor action, and whose functional importance has been borne out in many physiological studies. The SOCS box is a small part of the SOCS proteins that is believed to facilitate degradation of SOCS target proteins. The SPRY domain-containing SOCS box protein-2 (SSB-2) is one of four proteins within the greater SOCS family (SSB-1 to -4), which have a SOCS box and a centra ....The suppressor of cytokine signalling (SOCS) proteins, are intracellular molecules that negatively regulate hormone and growth factor action, and whose functional importance has been borne out in many physiological studies. The SOCS box is a small part of the SOCS proteins that is believed to facilitate degradation of SOCS target proteins. The SPRY domain-containing SOCS box protein-2 (SSB-2) is one of four proteins within the greater SOCS family (SSB-1 to -4), which have a SOCS box and a central SPRY domain. The SPRY domain mediates interaction with other proteins within the cell. Over 300 proteins are known to contain a SPRY domain. We recently determined the first atomic structure of a SPRY domain as part of SSB-2, using nuclear magnetic resonance (NMR) spectroscopy. We further identified Par-4 (prostate apoptosis response-4) as a novel and direct protein binding partner for SSB-1, -2 and -4, but not SSB-3. Extensive mutational analysis subsequently identified a series of SSB-2 mutants that were unable to bind Par-4 but retained structural integrity. Cancer cells develop through a series of genetic events and escape programmed cell death or apoptosis, continuing to grow inappropriately. Par-4 was originally discovered as a gene up-regulated in prostate cancer cells undergoing apoptosis and primarily appears to sensitise cancer cells to apoptotic stimuli. This proposal aims to further investigate SSB-Par-4 binding. The 3D structure of the complex will be determined and biochemical consequences of this interaction characterised. If SSB proteins regulate Par-4 levels, then chemical disruption of SSB-Par-4 binding could potentially result in an increase in Par-4 protein levels, making cancer cells more susceptible to killing by cytotoxic drugs.Read moreRead less
Inhibition Of Nef-activated Src-family Kinases By CHK
Funder
National Health and Medical Research Council
Funding Amount
$514,307.00
Summary
HIV hijacks infected blood cells to produce its own proteins. Nef is one of these proteins and Nef alone is sufficient to cause an AIDS-like disease. Recently, we discovered that a protein called CHK can inhibit Nef. Our research will determine how CHK inhibits Nef and test the feasibility of drugs based on CHK. Such drugs would slow AIDS progression, assisting conventional therapies and patients' immune systems to combat the infection, leading to longer, healthier, more productive lives.
Targeting genes elevated in the athlete's heart to improve function of the failing heart. Cardiovascular disease affects about 3.7 million Australians and heart failure ranks as one of the major killers, representing a huge burden on our health care system and economy. This situation is likely to get worse with an increasing ageing population. Current therapeutics for heart failure patients largely delay disease progression but generally fail in significantly improving heart function and quality ....Targeting genes elevated in the athlete's heart to improve function of the failing heart. Cardiovascular disease affects about 3.7 million Australians and heart failure ranks as one of the major killers, representing a huge burden on our health care system and economy. This situation is likely to get worse with an increasing ageing population. Current therapeutics for heart failure patients largely delay disease progression but generally fail in significantly improving heart function and quality of life. The proposal has focused on targeting the protective effects of 'good' heart growth by identifying genes elevated in the heart in response to exercise. Targeting genes elevated in the athlete's heart to improve function of the failing heart represents a new strategy for the treatment of heart failure.Read moreRead less
Novel G-protein Coupled Receptor Interactions And Complexes With Distinct Function And Pharmacology
Funder
National Health and Medical Research Council
Funding Amount
$246,760.00
Summary
G protein coupled receptors (GPCRs) are the target in the human body for most of today's medicines. Almost all pharmaceutical companies market drugs that are GPCR agonists or antagonists aimed at diverse disease states. Our research is focused on the molecular basis of drug recognition and signalling by GPCRs. We use genetic engineering techniques to create new receptors and mutant receptors in order to identify the functional domains of these signalling molecules. We have recently established a ....G protein coupled receptors (GPCRs) are the target in the human body for most of today's medicines. Almost all pharmaceutical companies market drugs that are GPCR agonists or antagonists aimed at diverse disease states. Our research is focused on the molecular basis of drug recognition and signalling by GPCRs. We use genetic engineering techniques to create new receptors and mutant receptors in order to identify the functional domains of these signalling molecules. We have recently established a novel approach based on proximity-dependent fluorescent technologies to explore receptor interactions and have described the formation of functional G-protein coupled complexes in living cells. This project is to discover new receptor combinations which could potentially affect signalling pathways and redirect cellular responses. Investigation of the mechanisms involved in turning on and off the body s response to stimuli would provide valuable information for drug design and treatment of GPCR-related conditions. We have chosen to use two GPCRs as models for our study of the mechanisms controlling receptor driven cellular responses and the interactions between cellular components-proteins behind this control. Firstly, the gonadotropin releasing hormone receptor (GnRHR), a protein located in the pituitary which is pivotal in the control of reproduction and secondly, the thyrotropin releasing hormone receptor (TRHR), similarly located and involved in modulating thyroid and metabolic function. We will investigate the way these receptors interact with other cellular proteins in order for them to function. Ultimately this will provide a better understanding of how these clinically important proteins function and pave the way for the development of clinical applications that target these receptor systems, resulting in the effective treatment of a wide range of conditions and diseases, including pain, migraine, certain forms of cancer, neurological and reproductive disorders.Read moreRead less