Metallothiol transferase FosB: Difference between revisions

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== DeltaFosB ==
== DeltaFosB ==


'''FIGURE:'''
'''INTRODUCTION'''  
This is a crystal structure of FosB from ''Staphylococcus aureus''.  This is a similar structure to DeltaFosB, although it retains 2 destabilizing elements which are spliced in the DeltaFosB variant. The DeltaFosB transcription factor should include 3 domains: a transactivating domain, a DNA binding domain, and a signal sensing domain. DeltaFosB includes is a basic motif, a Leucine zipper, and a bZIP domain scene


PDB ID: 4NB0
<Structure load='4NB0' size='500' frame='true' align='right' caption='Structure of FosB in Staphylococcus aureus (PDB code [[4NB0]])' scene='Insert optional scene name here' />
Structure and Function of the Genomically Encoded Fosfomycin Resistance Enzyme, FosB, from Staphylococcus aureus.
(2014) Biochemistry 53: 755-765
 
'''INTRODUCTION'''  


The transcription factor, DeltaFosB, is known to be involved in some of the physiological mechanisms linked to addiction and compulsive behaviors. Levels of DeltaFosB have been shown to increase in multiple regions of the brain in response to repeated drug exposure as well as stress, certain antipsychotic or antidepressant medications, electroconvulsive seizures, and certain lesions. DeltaFosB is a truncated, highly stable splice variant of the FosB transcription factor whose expression is regulated by alternative splicing of the FosB gene. Due to this splicing, DeltaFosB is known to have a half life five times that of FosB, which is thought to be a basis for addiction.
The transcription factor, DeltaFosB, is known to be involved in some of the physiological mechanisms linked to addiction and compulsive behaviors. Levels of DeltaFosB have been shown to increase in multiple regions of the brain in response to repeated drug exposure as well as stress, certain antipsychotic or antidepressant medications, electroconvulsive seizures, and certain lesions. DeltaFosB is a truncated, highly stable splice variant of the FosB transcription factor whose expression is regulated by alternative splicing of the FosB gene. Due to this splicing, DeltaFosB is known to have a half life five times that of FosB, which is thought to be a basis for addiction.
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Alternative splicing removes two destabilizing elements from FosB generating the more stable DeltaFosB transcription factor. A 140-nucleotide sequence is removed from exon 4 of the primary FosB transcript, resulting in a one-nucleotide frameshift and the formation of an early stop codon (TGA). This results in premature termination of normal FosB translation; therefore, proteins translated from DeltaFosB mRNA are missing an important amino acid sequence which is normally present towards the C-terminal of full-length FosB proteins. FosB contains a sequence of amino acids (278-337) that is normally targeted for degradation by proteasomes. The DeltaFosB variant lacks this sequence resulting in increased stability as it is not recognized and therefore not degraded by proteasomes. The other region identified for destabilization of FosB, independent of preteasome degradation, is a sequence of amino acids (238-277). The mechanism for destabilization in this region is not as well understood as the proteasome-dependent destabilizing region<ref>Carle, T. L., Ohnishi, Y. N., Ohnishi, Y. H., Alibhai, I. N., Wilkinson, M. B., Kumar, A. and Nestler, E. J. (2007) Proteasome-dependent and -independent mechanisms for FosB destabilization: identification of FosB degron domains and implications for ΔFosB stability. European Journal of Neuroscience, 25, 3009–3019. doi: 10.1111/j.1460-9568.2007.05575.x</ref>.  
Alternative splicing removes two destabilizing elements from FosB generating the more stable DeltaFosB transcription factor. A 140-nucleotide sequence is removed from exon 4 of the primary FosB transcript, resulting in a one-nucleotide frameshift and the formation of an early stop codon (TGA). This results in premature termination of normal FosB translation; therefore, proteins translated from DeltaFosB mRNA are missing an important amino acid sequence which is normally present towards the C-terminal of full-length FosB proteins. FosB contains a sequence of amino acids (278-337) that is normally targeted for degradation by proteasomes. The DeltaFosB variant lacks this sequence resulting in increased stability as it is not recognized and therefore not degraded by proteasomes. The other region identified for destabilization of FosB, independent of preteasome degradation, is a sequence of amino acids (238-277). The mechanism for destabilization in this region is not as well understood as the proteasome-dependent destabilizing region<ref>Carle, T. L., Ohnishi, Y. N., Ohnishi, Y. H., Alibhai, I. N., Wilkinson, M. B., Kumar, A. and Nestler, E. J. (2007) Proteasome-dependent and -independent mechanisms for FosB destabilization: identification of FosB degron domains and implications for ΔFosB stability. European Journal of Neuroscience, 25, 3009–3019. doi: 10.1111/j.1460-9568.2007.05575.x</ref>.  


<Structure load='4NB0' size='500' frame='true' align='right' caption='Structure of FosB in Staphylococcus aureus (PDB code [[4NB0]])' scene='Insert optional scene name here' />
'''FIGURE:'''
This is a crystal structure of FosB from ''Staphylococcus aureus''.  This is a similar structure to DeltaFosB, although it retains 2 destabilizing elements which are spliced in the DeltaFosB variant. The DeltaFosB transcription factor should include 3 domains: a transactivating domain, a DNA binding domain, and a signal sensing domain. DeltaFosB includes is a basic motif, a Leucine zipper, and a bZIP domain scene
 
PDB ID: 4NB0
Structure and Function of the Genomically Encoded Fosfomycin Resistance Enzyme, FosB, from Staphylococcus aureus.
(2014) Biochemistry 53: 755-765
 




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