Proteins Using Different Residues in the Same/Overlapping Site for Different Functions

Moonlighting proteins in this category are multidomain proteins (listed in Table 2.4) which utilize overlapping functional sites for carrying out their primary and moonlighting function(s).

Phosphoglucose isomerase, Oryctolagus cuniculus, Mus musculus, Homo sapiens

Phosphoglucose isomerase (PGI, EC 5.3.1.9) is a glycolytic enzyme which catalyses the interconversion of glucose-6-phosphate and fructose-6-phosphate (Function 1). It is known to moonlight as an autocrine motility factor (tumor-secreted cytokine that promotes cellular growth and motility), neuroleukin (a neurotrophic factor

Leukotriene A4 hydrolase

Figure 2.10 Leukotriene A4 hydrolase. The LTA4 catalytic site residues Glu296 and Tyr383 are shown in blue. The catalytic site residue Glu271, involved in two separate functions in two different catalytic reactions is shown in red (PDB:2R59). (See color plate section for the color representation of this figure.)

Phosphoglucose isomerase

Figure 2.11 Phosphoglucose isomerase (PGI). Catalytic residues are shown as red sticks. Inhibition of enzymatic and AMF functions of PGI by the PGI inhibitor and mutational analysis of the catalytic residues have indicated overlapping regions of both functions in the human PGI (PDB:1IAT). (See color plate section for the color representation of this figure.)

for neurons), and differentiation mediator in mammals (Function 2) [48]. The human PGI exists as a dimer comprising three domains: two (one large and one small) Rossman fold domains and an a-orthogonal bundle [49] (Fig. 2.11). The known catalytic site residues are Lys210, Glu216, Gly271, Arg272, Glu357, His388, and Lys518 (1IAT). The PGI inhibitor erythrose-4-phosphate (E4P) is known to inhibit both the enzymatic and cell motility activities of PGI. Moreover, mutation of the catalytic residues resulted in significant reduction in the AMF or cell-motility-stimulating activity.

Aldolase, Plasmodium falciparum

The fructose-bisphosphate aldolase (EC 4.1.2.13; Function 1) from apicompl- exan parasites such as P. falciparum and P vivax also provides a bridge between the actin filaments and TRAP (thrombospondin-related anonymous protein), which is critical for the host invasion machinery of the malaria parasite (Function 2) [50]. The P falciparum aldolase structure consists of four chains, each consisting of a TIM barrel domain (Fig. 2.12). The aldolase active site residues and the residues involved in binding actin or TRAP overlap are located in the centre of the TIM barrel. The aldolase active site comprises the residues Asp39, Lys112, Glu194, and Lys236. The actin-binding residues of aldolase are Arg48, Lys112, Arg153, and Lys236 and the TRAP binding residues are Glu40, Lys47, Arg48, Lys151, Arg153, Arg309, and Gln312.

 
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