Human recombinant prothymosin alpha (ProT alpha) is known to have coil-like conformation at neutral pH; i.e., it belongs to the class of "natively unfolded" proteins. By means of circular dichroism, SAXS, and ANS fluorescence, we have investigated the effect of several divalent cations on the structure of this protein. Results of these studies are consistent with the conclusion that ProT alpha conformation is unaffected by large excess of Ca2+, Mg2+, Mn2+, Cu2+, and Ni2+. However, Zn2+ induces compaction and considerable rearrangement of the protein structure. This means that ProT alpha can specifically interact with Zn2+ (K-D similar to 10(-3) M), and such interactions induce folding of the natively unfolded protein into a compact partially folded (premolten globule-like) conformation, It is possible that these structural changes may be important for the function of this protein.