Plasmodia express two threonine-peptidase complexes during asexual development.
Threonine-peptidases of the T1-family are multi-subunit complexes with broad substrate specificity. In eukaryotes, at least 14 genes encode subunits of the prototypic T1 threonine-peptidase, the proteasome. The proteasome determines the turnover of most proteins and thereby plays a fundamental role in diverse processes such as protein quality control, signal transduction, and cell cycle regulation. While eukaryotes and archaea possess a proteasome, bacteria generally express a second member of the T1-family, the proteasomal predecessor ClpQ/hslV that has a similar structure but is encoded by only one gene. The plasmodial genome is an exception because it encodes proteasomal subunits as well as a ClpQ/hslV-orthologe (Plasmodium falciparum-hslV; PfhslV). Structure, expression, and function of both types of peptidase-complex in P. falciparum are presently unknown. Our aim was to analyze both the coding sequences and derived proteins of both peptidase-complexes because highly specific and potent inhibitors can be designed against this class of enzymes. The proteasome was found expressed throughout the cell cycle, whereas PfhslV was detectable in schizonts and merozoites only. Treatment of P. falciparum with the threonine-peptidase inhibitor epoxomicin blocked two of three catalytically active proteasome subunits. This led to the accumulation of ubiquitinated proteins and, finally, to parasite death. In conclusion, we provide the first functional analysis of plasmodial threonine-peptidase-complexes and identify a lead compound for the development of a novel class of antimalarial drugs.
Mordmüller
Benjamin
B
University of Tübingen, Department of Parasitology, Germany. benjamin.mordmueller@uni-tuebingen.de
Fendel
Rolf
R
Kreidenweiss
Andrea
A
Gille
Christoph
C
Hurwitz
Robert
R
Metzger
Wolfram G
WG
Kun
Jürgen F J
JF
Lamkemeyer
Tobias
T
Nordheim
Alfred
A
Kremsner
Peter G
PG
D000595:Amino Acid Sequence; D000818:Animals; D020134:Catalytic Domain / Q000187:drug effects; D017125:Genes, Protozoan; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000494:pharmacology; D010447:Peptide Hydrolases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D010963:Plasmodium falciparum / Q000254:growth & development / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015800:Protozoan Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D013912:Threonine
D009842:Oligopeptides; D015800:Protozoan Proteins; D013912:Threonine; D010447:Peptide Hydrolases; D046988:Proteasome Endopeptidase Complex; C078846:epoxomicin