Folding autonomy of the kringle 4 fragment of human plasminogen.

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Abstract
Kringle 4, an 88-residue plasminogen fragment carrying a lysine-binding site, loses its affinity for lysine-Sepharose upon reductive cleavage of its disulfide bridges. Aerobic incubation of the reduced, denatured fragment results in the rapid restoration of the disulfide bonds with concomitant recovery of lysine-Sepharose affinity. The ability of the unfolded fragment to regain its native conformation suggests that the kringle structure is an autonomous folding domain. During refolding of kringle 4 the native disulfide bonds, .**GRAPHIC**. and .**GRAPHIC**. appear first. The folding intermediate possessing these 2 disulfide bridges already binds to lysine-Sepharose, indicating that the 3rd native bridge, which in native kringle 4 connects residues Cys1 and Cys79, is not essential for the maintenance of the biologically active conformation of kringle 4. Comparison of the sequences of human prothrombin, urokinase and plasminogen kringles revealed that the residues surrounding the .**GRAPHIC**. and .**GRAPHIC**. bridges constitute the most conservative segments of kringles, whereas the residues neighboring the .**GRAPHIC**. bridge are not highly conserved. Conservation of various residues in the different kringles apparently reflects their importance for the folding autonomy of kringles.

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