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DATABASES |
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| HISTORY OF SERPIN |
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In 1980 Hunt and Dayhoff made the surprising discovery that both these molecules share significant amino acid sequence similarity to the major protein in chicken egg white, ovalbumin, and they proposed a new protein superfamily. Over 1000 serpins have now been identified; these include 36 human proteins, as well as molecules in plants, fungi, bacteria, archaea and certain viruses. Serpins are thus the largest and most diverse family of protease inhibitors.
The term serpin is used to describe these latter members as well, despite their noninhibitory function.
Serpin polymerisation reduces the amount of active inhibitor, as well as accumulation of serpin polymers causing cell death and organ failure.
Some serpins inhibit other classes of protease and are termed "cross class inhibitors". Most notably a number of such serpins have been shown to target cysteine proteases. These enzymes differ from serine proteases.
Approximately two thirds of human serpins perform extracellular roles.
Non-inhibitory extracellular serpins also perform important roles.
The protease targets of intracellular inhibitory serpins have been more difficult to identify. Characterisation is complicated by these molecules appearing to perform overlapping roles, as well as the lack of precise functional equivalents of human serpins in model organisms such as the mouse.
Intracellular serpins also perform roles distinct from protease inhibition.
When attacking a substrate, serine proteases catalyze peptide bond cleavage in a two-step process.
The conformational mobility of serpins provides a key advantage over static lock and key protease inhibitors. In particular, the function of inhibitory serpins can be readily controlled by specific cofactors.
The partially inserted conformation is important because co-factors are able to conformationally switch partially inserted serpins into a fully expelled form. This conformational rearrangement makes the serpin a more effective inhibitor.
Certain serpins spontaneously undergo the S to R transition as part of their function, to form a conformation termed the latent state. Latent serpins are unable to interact with proteases and are not protease inhibitors.
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| SLIDE SHOW |
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