Structure, Transport And Assembly Of PorB, A Key Invasion Molecule Of Meningococcal Disease
Funder
National Health and Medical Research Council
Funding Amount
$292,639.00
Summary
When the bacteria that cause meningococcal disease invade cells, they use specialized cell surface pore proteins to hijack the human cell and maintain infection. This research will study the structure of these bacterial pore proteins to help understand how they function to subvert normal cellular processes, and this insight will be important in the development of new treatments for meningococcal disease.
Structural Characterisation Of Phosphopeptide Recognition By FHA Domains
Funder
National Health and Medical Research Council
Funding Amount
$257,036.00
Summary
Cells require numerous signalling pathways to keep various cellular processes coordinated and under control. One of the most important aspects of signalling is formation of complexes involving two or more different proteins. One of the recently identified players in the formation of these signalling complexes is the so-called forkhead-associated (FHA) module, FHA modules are protein sequences of ~130 amino acids that appear as a part of signalling proteins and bind to specific sequences on signa ....Cells require numerous signalling pathways to keep various cellular processes coordinated and under control. One of the most important aspects of signalling is formation of complexes involving two or more different proteins. One of the recently identified players in the formation of these signalling complexes is the so-called forkhead-associated (FHA) module, FHA modules are protein sequences of ~130 amino acids that appear as a part of signalling proteins and bind to specific sequences on signalling protein partners. Many proteins containing FHA modules are important for the repair of damaged DNA and the stability of chromosomes. The aim of our studies is to understand the molecular and atomic details of how FHA modules bind their partners. This is the first step towards designing therapeutic agents against various forms of cancer where DNA is damaged.Read moreRead less
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