Distribution of proline-rich (PxxP) motifs in distinct proteomes: functional and therapeutic implications for malaria and tuberculosis.
We have conducted a survey of proline-rich (PxxP) motifs in the proteomes of human, mouse, yeast, Mycobacterium tuberculosis and Plasmodium falciparum. Our analyses reveal a strikingly high occurrence of these motifs in each organism, suggesting a wide dependence on protein-protein interaction networks in cellular systems. All proteomes considered have an abundance of PxxP motifs which can potentially participate in binding to SH3 domain-containing proteins. A large fraction of these motifs can be assigned to structurally conserved types of class I and class II sequences. We propose that while maintaining the primary biochemical function, many proteins are likely to participate in additional interactions involving molecular cross-talk with other proteins using proline-rich and other motifs. We have also identified PxxP-containing motifs that are unique to P.falciparum and M.tuberculosis. These sequences may serve as leads for the development of peptidomimics that specifically target these organisms. We propose a novel drug target selection strategy where shared PxxP-containing motifs can be used to direct the development of inhibitors that focus on multiple targets in the cell. Screening for such unique PxxP-containing motifs in the P.falciparum proteome yielded highly conserved sequences in the variant surface antigen family that can be used to initiate design of peptidomimics that may potentially abrogate parasite cytoadherence during malaria infections.
Ravi Chandra
Beeram
B
Malaria Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi-110067, India.
Gowthaman
Ramasamy
R
Akhouri
Reetesh Raj
RR
Gupta
Dinesh
D
Sharma
Amit
A
D020816:Amino Acid Motifs; D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology; D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology; D001426:Bacterial Proteins / Q000737:chemistry / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D008288:Malaria / Q000188:drug therapy; D008958:Models, Molecular; D018716:Molecular Mimicry; D009169:Mycobacterium tuberculosis / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000737:chemistry*; D011392:Proline; D011487:Protein Conformation; D020543:Proteome / Q000737:chemistry*; D015800:Protozoan Proteins / Q000737:chemistry / Q000187:drug effects; D014376:Tuberculosis / Q000188:drug therapy
D000962:Antimalarials; D000995:Antitubercular Agents; D001426:Bacterial Proteins; D010455:Peptides; D020543:Proteome; D015800:Protozoan Proteins; D011392:Proline