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PEDS Advance Access published online on February 20, 2004
Protein Engineering Design and Selection, doi:10.1093/protein/gzh024
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Received October 22, 2003
Revised January 6, 2004
Accepted February 2, 2004
Oxford University Press

Article

Distribution of proline-rich (PxxP) motifs in distinct proteomes: functional and therapeutic implications for malaria and tuberculosis

Beeram Ravi Chandra 1, Ramasamy Gowthaman 1, Reetesh Raj Akhouri 1, Dinesh Gupta 1, and Amit Sharma 1*

1 Malaria group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi-110067, India


  Abstract

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 wide dependence on protein-protein interaction networks in cellular systems. All considered proteomes 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 designated into 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 Plasmodium falciparum and Mycobacterium 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 Plasmodium 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.

Keywords: Protein-protein interactions/PxxP motifs/ peptidomimics/signal transduction/ SH3 modules


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