Conformational Changes

Conformational Changes in Proteins - V

A substantial conformational change upon cleavage of the protein chain certainly is understandable, if unusual, since the two structures do not have the same primary chemical bonds.

As introduced on the previous page, however, the serpins offer a third possibility - a latent state.

Under physiological conditions, the active forms of these proteins are metastable

Within times of the order of hours, they convert spontaneously to a "latent" form that is inactive

The implication is that the native state is an intermediate in the folding of the serpins to the most stable state, the latent form

This observation challenges the idea that the native state must be substantially lower in energy than all other conformations

The stable latent form closely resembles the cleaved conformation, save that the loop that inserts between several b-strands is not cleaved.

Human Antitrypsin (1ez2), Stable Conformation

This answers the question of where the energy comes from to drive the rearrangement.

Thrombin is a serine protease involved in blood clotting. It has a serpin inhibitor just like antitrypsin:

Active Antithrombin (2ant)	Latent Antithrombin (2ant)

Again the core of the structure remains largely unchanged; the rmsd 1.19 A:

Alignment of Active and Latent Antithrombin

The change is initiated by binding of heparin or other oligosaccharides to the protein.

An exception to this behavior is ovalbumin, which does not form a latent state, nor, when cleaved, does it insert the cleaved loop among the b-strands.

Ovalbumin

Despite the difference in behavior, much structural similarity exists between ovalbumin and the other serpins. Here, for example, is a superposition with native antitrypsin:

Superposition of Antitrypsin and Ovalbumin

The rms is 1.13 A. Much sequence similarity (30% identity, 52% similarity) also exists, as shown in the alignment below (from BioEdit):

Sequence Alignment of Antitrypsin and Ovalbumin

Convergent or divergent evolution?

This page last modified 11:10 AM on Friday March 2nd, 2012.
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