Chemistry Reference
In-Depth Information
use available information on the structure of genes, proteins, and functional rela-
tionships between them. Investigation of PPIs by means of computer-based methods
allows verification or confirmation of experimental results to avoid false-positive
and/or false-negative conclusions and it can serve to assess the validity of possible
interacting partners.
There are many computer-based tools and algorithms for prediction of PPIs allow-
ing identification of interface residues and assignment of protein functions to genes
are also possible. Investigation of PPIs through computer-based methods involves
a few basic steps: (i) the retrieval of the amino acid sequences of the proteins of
interest, (ii) generation of three-dimensional models of the proteins of interest, (iii)
models optimization and validation.
For the estimation of PPIs we must take into account the genomic sequence
analysis and associated physicochemical properties of amino acids (Pazos et al.
1997
), and recognition of specific residue motifs (Kini and Evans
1996
).
Today, there are numerous databases of PPI data such as: database of inter-
acting proteins—DIP (Xenarios et al.
2002
), biomolecular interaction network
database—BIND (Bader et al.
2003
), general repository for interaction datasets—
GRID (Breitkreutz et al.
2003
), Saccharomyces genome dataset-SGD (Christie et al.
2004
), and human protein reference database—HPRD (Peri et al.
2004
).
Proteins bind together through a combination of physicochemical interactions:
hydrophobic bonding, van der Waals forces and salt bridges. There also are specific
binding domains on each interacting protein. These domains are either binding clefts
and can be a few peptides long, either large surface spanning hundreds of amino
acids. The size of the binding domains is very important as it influences the strength
of the binding.
There are several typical protein-protein interaction motifs. Such a motif is the
leucine zipper, which consists of
-helices on each protein that bind to each other
in a parallel fashion through the hydrophobic bonding of regularly-spaced leucine
residues on each
α
-helix interdigitating into the adjacent helix, forming a stable
coiled-coil (Phizicky and Fields
1995
). Figure
9.10
illustrates the leucine zipper
structural motif for the dimer of general control protein GCN4 from
Saccharomyces
Cerevisiae
, PDB code entry 1ZIK (Gonzales et al.
1996
) visualized using Chimera
software. Leucine zippers provide a tight and stable molecular binding for multi-
protein complexes and also for protein-DNA complexes.
Another motif involved in protein-protein interactions is the SH2 domain. It is
a motif of about 100 amino acids belonging to Src-protein and also found in many
other proteins being involved in the recognition of proteins and peptides containing
phosphorylated tyrosines (Phizicky and Fields
1995
). This motif is presented in
Fig.
9.11
for the SH2-domain of human cytoplasmic protein NCK2 (blue ribbon)
in complex with a decaphosphopeptide (magenta, atoms ball and sticks), PDB code
entry 1CIA (Frese et al.
2006
). Src protein also contains a SH3 binding motif, a
noncatalytic domain which is involved in protein-protein interactions and is found
in many proteins. Its length varies between about 55 and 75 amino acids, and its
structure contains antiparallel sheets, as it is illustrated in Fig.
9.12
for the SH3
domain of human Lyn-tyrosine kinase, PDB code entry 1WIF (Bauer et al.
2005
).
α
