Abstract
The three-dimensional fold of Plasmodium falciparum (Pf) 20S proteasome is similar to yeast Saccharomyces cerevisiae 20S proteasome. The twenty eight subunits complex corresponding to two copies of seven distinct α and seven distinct β subunits shares >35% sequence identity with equivalent subunits of the yeast 20S proteasome. Bortezomib (Velcade®) – a known inhibitor of the three catalytic subunits; β1, β2, β5 of the yeast 20S proteasome can bind in the equivalent subunits of the Pf 20S proteasome and is in agreement with experimental results. The model defines the binding mode of the bortezomib inhibitor within the catalytic subunits of the Pf 20S proteasome and provides the structural basis for the design of Pf 20S proteasome-specific inhibitors. The substitutions associated within the catalytic subunits of Pf 20S proteasome relative to yeast 20S proteasome; Thr21-Ser, Thr22-Ser, Thr31-Ser, Thr35-Asn, Ala49-Ser (in β1 subunit), Ser20-Ala, Gln22-Glu (β2) and Thr21-Ser, Ala22-Met, Gln53-Leu (β5) may influence the relative caspase-like, tryptic-like and chymotryptic-like activities of the Pf 20S proteasome. The plasmodia-specific 'large’ insert comprising fifty four amino acid residues (in β1 subunit) of the Pf 20S proteasome is distant from the catalytic sites.
Highlights
An essential element of the protein quality control machinery in cells is the ubiquitin-proteasomal system (Hershko & Ciechanover 1998; Pickart 2001; Myung et al 2001)
Proteasomes (Wolf & Hilt 2004) are protein degradative machines found in the nucleus and cytoplasm of all eukaryotic organisms and archaebacteria and is a highly organized protease complex comprising a catalytic 20S core particle (CP) and two 19S regulatory particles (RP), which together form the 26S structure
The three-dimensional model of the Plasmodium falciparum (Pf) 20S proteasome complexed with the bortezomib inhibitor supports previous experimental studies that demonstrate bortezomib inhibition of the Pf 20S proteasome and further elucidates its binding mode within the catalytic subunits
Summary
An essential element of the protein quality control machinery in cells is the ubiquitin-proteasomal system (Hershko & Ciechanover 1998; Pickart 2001; Myung et al 2001). Proteasomes (Wolf & Hilt 2004) are protein degradative machines found in the nucleus and cytoplasm of all eukaryotic organisms and archaebacteria and is a highly organized protease complex comprising a catalytic 20S core particle (CP) and two 19S regulatory particles (RP), which together form the 26S structure. The core particle degrading machinery in yeast Saccharomyces cerevisiae 20S proteasome is coded by fourteen genes and two copies of these constitute the twenty eight subunits in the complex. The complete subunit architecture of the yeast regulatory particle provides a model for the recognition, deubiquitination and engagement of a polyubiquitinated substrate by the 26S proteasome (Lander et al 2012). The proteasome is a potential target for treating many infections and diseases (Dahlmann 2007)
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