Serine Proteases: Introduction and Overview

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Web site
This site is dedicated to analyzing correlations between sequence, structure, evolution and function of serine proteases. It is not an archive (some very good ones are in the links), but creates dynamic links between data. Different options are available in the search menu to look for all kind of informations (sequences, structures, functions, mutations, organisms, publications...) in internal and external databases through direct forms. A collection of search engines are also directly indexed there.

Examples of problems that can be approached using this web site are illustrated in the Tour and Tutorials:
Which residues from a set of aligned sequences are associated with a given activity, ligand binding or other specified properties ?
When or how was this property acquired through evolution ?
What is the likely substrate specificity of a protease based on its sequence and its structure?

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Serine proteases
Proteases, proteinases or peptidases describe the same group of enzymes that catalyse the hydrolysis of covalent peptidic bonds. In the case of serine proteases the mechanism (from Mellon College of Science Courses) is based on nucleophilic attack of the targeted peptidic bond by a serine. Cysteine, threonine or water molecules associated with aspartate or metals may also play this role. In many cases the nucleophilic property of the group is improved by the presence of a histidine, held in a "proton acceptor state" by an aspartate. Aligned side chains of serine, histidine and aspartate build the catalytic triad common to most serine proteases.

The active site of serine proteases is shaped as a cleft where the polypeptide substrate binds. Schechter and Berger [1] labeled amino acid residues from N to C term of the polypeptide substrate (Pi, ..., P3, P2, P1, P1', P2', P3', ..., Pj) and their respective binding sub-sites (Si,..., S3, S2, S1, S1', S2', S3',..., Sj) . The cleavage is catalyzed between P1 and P1'.
Many proteases are synthesized and secreted as inactive forms called zymogens and subsequently activated by proteolysis. This changes the architecture of the active site of the enzyme.
Serine proteases are sequence specific. While cascades of protease activations control blood clotting and complement, other proteasesare involved in signalling pathways, enzyme activation and degradative functions in different cellular or extracellular compartments.

Classification
Rawlings and Barrett [2,3] have proposed a classification of proteases in families and clans.
Families group sequences according to the alignment score of their catalytic domains. A sequence belong to a family if significance score of BLAST [4] is less than 0.0001 or greater than 6.0 for RDF [5] and ProfilSearch [6], with at least one of the catalytic domains of the sequence family. Serine proteases are coded from S1 to S35. Sub-families classify deeply divergent groups from the same family, as indicated by letters such as S2A, S2B, etc...
Clans, coded from SA to SF, group families with the same order of catalytic residues along the sequence and show the same 3D-fold of the catalytic domain. Proteases of the same clan should have a common ancestor. Global classifications of proteases are accessible in the Merops [7] and ExPASy [8] websites. An overview of the classification of serine proteases is displayed in the sequence index page of this site.

References

Schechter and Berger (1967) BBRC.27:157-162.
Rawlings N.D., Barrett A.J. (1993) Evolutionary families of peptidases.
Biochem. J. 290:205-218.
Rawlings N.D., Barrett A.J. (1994) Families of serine peptidases. Meth. Enzymol. 244:19-61.
Blast website (1999) http://www.expasy.ch/cgi-bin/lists?peptidas.txt
RDF website (1999) http://www.expasy.ch/cgi-bin/lists?peptidas.txt
ProfilSearch website (1999) http://www.expasy.ch/cgi-bin/lists?peptidas.txt
Merops website (1999) http://www.bi.bbsrc.ac.uk/Merops/Merops.htm
ExPASy website (1999) http://www.expasy.ch/cgi-bin/lists?peptidas.txt

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Go to the Department of Biochemistry and Molecular Biophysics

Thierry Rose, PhD and Enrico Di Cera, MD
Department of Biochemistry and Molecular Biophysics
Washington University School of Medicine
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