Proteasomes are instrumental in degradation of damaged or non functional proteins and a variety of other regulatory functions. They comprise of various enzymes which breakdown the proteins into its constituent amino acids.
Because of its multifunctional role and multi subunit nature, the proteasomes are of immense research potential. They are found to be instrumental in viral infections including HIV and hence drug designing approaches using proteasomes are promising.
HIV and proteasomes
HIV virus is one of the classical viruses which employ proteasomes for their infection. The virus has three protein complexes responsible for producing the inner virion core (Gag), the viral enzymes (Pol), and the external glycoprotein envelope (Env).
HIV virus enters the host cell and the genome gets translated. The newly formed Gag protein gets cleaved by proteasomes into matris, capsid and nucleocapsid along with p6 gag proteins. Proteasomes thus function to produce the infectious viral particles.
Selective degradation by proteasomes is often mediated through covalent binding of ubiqutin to the protein and this is employed by HIV. The virus protein Vpu labels the CD4 molecules with ubiquitin making them vulnerable to degradation by proteasomes. CD4 molecules are involved in identification of virally infected cells by T cells and prevent their destruction.
Moreover, the proteasomes are found to play both proteolytic and non proteolytic types of regulation of HIV-1 promoter. The transcription factor, Tat was found to dissociate the proteasomes into its subunits through a mediator proteasome associated protein, PAAF-1. This in turn inhibited the proteolytic activity. Tat also interferes with Class-I presentation of some epitopes. Drugs such as ritonavir block the presentation of viral antigens to Cytotoxic T lymphocytes.
The Proteasome association in gene regulation and selective protein degradation had led to the development of proteasome inhibitors as drugs.
Proteasome subunits have different catalytic functions. The inhibitors target these activities which are similar to trypsin, chymotrypsin and the hydrolysis of peptidyl glutamyl peptide bonds. Some of the inhibitors are naturally occurring while others are designed using various approaches of drug designing.
TMCs, Hsp 90, P131 etc are naturally occurring proteasomal inhibitors. Binding site of TMCs is adjacent to the Threonine active site of the enzyme. Hsp 90 inhibits the chymotrypsin like activity and peptidyl glutmyl peptide hydrolysis activity of the 20S subunit.
They are also instrumental in regulation of cell cycle and induction of apoptosis. Proteasomes are therefore potential targets for drug designing approaches for cancer.
They are being recognized as potential drug targets in tuberculosis due to the similarity of the mycobacterial proteasomes with that of eukaryotes. M. Tuberculosis is the only bacterial pathogen known to possess proteasomes.
The use of proteasome inhibitors as anti infectives have so far not been materialized since it is difficult to avoid the inherent risk associated with blocking the natural proteasomes which are important for maintaining cellular activities such as apoptosis. Proteasomal non functioning is also present in neurodegenerative diseases such as Parkinson's, Huntngton's disease etc. This is thought to cause an increase in the protein turn over which can result in death of nervous tissue.
Proteasomes and evolution
These structures are present in primitive organisms such as archebacteria. Euacteria have complex protein degrading machinery with 14 different proteins of 7 alpha and 7 beta chains. However the archebacterial proteasomes have only two proteins with 14 copies of each.
The sequences are comparatively preserved across the species and therefore phylogenetic analyses reveal information on evolutionary history. The subunits alpha and beta are thought to origin as a result of single gene duplication event which must have occurred prior to the divergence of archaebacteria and eukaryotes. The conserved sequence within a single structure is considered as a proof for this view.
The core 20S particle is similar with four ring structures in both archaebacteria and eukaryotic cells. However 20S subunit is made of two peptide chains alone in arachaebacteria. There is a single ATPase called PAN which serves the function in arachaebacteria while in eukaryotes this is replaced by six ATPases.
Study of proteasomes has become more relevant to exploration of evolutionary history with the identification of more primitive organisms. Malfunction of Ubiquitin-proteasome system is found to be associated with many diseases. The involvement of proteasomes in metabolic regulation is also being evident from research studies. This makes them ideal targets for drug designing along with development of methods to reduce the toxicity attributes.
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