SPRY domain-containing SOCS box (SSB) protein interaction with Par-4: Structure and biochemical implications

Funded Activity 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 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.

Funded Activity Details

Start Date: 01-01-2007

End Date: 01-01-2009

Funding Scheme: NHMRC Project Grants

Funding Amount: $529,565.00

Funder: National Health and Medical Research Council

Research Topics

ANZSRC Field of Research (FoR)

Protein Targeting And Signal Transduction

ANZSRC Socio-Economic Objective (SEO)

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Other Keywords

apoptosis | biochemistry and molecular biology | cancer | gene structure/protein function/novel drug therapies | growth factors | immunology | nuclear magnetic resonance (NMR) | protein structure | protein-protein interaction | signalling

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