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Multiple Alignment of Protein-Protein InterfaceS (PPIs)
Recognizes spatially conserved chemical interactions shared by a set of PPIs


A protein-protein interface (PPI) is defined by a pair of regions of two interacting protein molecules that are linked by non-covalent bonds. Recognition of conserved 3D patterns of physico-chemical interactions may suggest their importance for the function as well as for the stability and formation of the protein-protein complex. It may assist in discovery of new drug leads that target these interactions.

MAPPIS is a novel method for multiple structural alignment of PPIs which allows recognition of a set of common physico-chemical properties and their interactions without the need to assume similarity of sequential patterns or backbone patterns. We show its application to several biological examples, such as alignment of interfaces of G proteins with their effectors and regulators, as well as previously created clusters of interfaces.

Biological Motivation:

There are examples of proteins that have totally different overall sequences and folds, but create similar interactions with their corresponding binding partners, which may also have different overall sequences and folds.
On of the most well studied examples of such interfaces are those created by proteins of the functional family of serine proteases, which belong to two different structural folds, trypsin-like and subtilisin-like, but perform similar functions and have similar catalytic residues. The figure presents an alignment, obtained by MAPPIS, between 6 PPIs of serine proteases, with proteins from two different folds Trypsin-like serine proteases (4sgb, 1ppf, 1acb, blue and red) and Subtilisin-like (1cse, 2sic, 1oyv, green and yellow). The rightmost figure presents the common physico-chemical properties and the conserved interactions between them. The residues that are conserved in sequence in all the proteins are annotated according to PDB:4sgb. The MAPPIS solution is correct due to the correct alignment of the catalytic residues of these proteins. The advantage of MAPPIS is in the analysis of similarity of the created interactions, which are presented in the rightmost figure.

Alexandra Shulman-Peleg