6706 Nucleic Acids Research, 2006, Vol. 34, No. 22 Figure 7. Two models for the function of the 2TM proteins. In the upper panel (A) the proteins participate in formation of a multi-subunit, multi-TM solute pore. An alternative model is proposed in which the 2TM proteins modulate endogenous erythrocyte solute channels. In the lower panel (B) the proteins form the knob structure containing PfEMP1 proteins and mediating cytoadherence. A third model might integrate the knob and solute pore and knobs into a single erythrocyte surface structure. of over 200 genes to encode the catalog of 2TM proteins sug- gests that these proteins participate in the formation of a criti- cal erythrocyte surface structure, perhaps forming a transmembrane anchor for the knob that underpins PfEMP1- mediated cytoadherance, or 2TM subunits of a multi-subunit, multi-transmembrane erythrocyte surface solute channel (Figure 7). Our observations from immunoelectron localiza- tion studies of chimeric 2TM proteins suggest that erythrocyte surface expression is not relegated solely to knobs (Figure 3), albeit these studies were performed following the overexpres- sion of transgenic epitope-tagged 2TM proteins. SUPPLEMENTARY DATA Supplementary data are available at NAR Online ACKNOWLEDGEMENTS We are grateful to Stephane Egee for his considerable help in the construction of expression plasmids and for valuable discussions. Dr Karen Hayton (NIAID/NIH) is thanked for the generous gift of genomic DNA from P.falciparum isolates. Dr Matthew Berriman (The Wellcome Trust Sanger Institute) is thanked for allowing use of the genome sequence data for the P.falciparum Ghanaian isolate. The Broad Institute is thanked for providing to the scientific community the genome sequence for the P.falciparum HB3 isolate. T.J.T. would like to acknowledge the support of the William Randolph Hearst Foundation. 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