Structural Biochemistry/Protein-Protein Interaction Network
Protein-protein interaction network is bindings of multiple proteins with distinct conformation (3D structure). A node in the network represents a protein and a node that can interact with ten to hundreds of other nodes is considered a hub protein. A hub protein is essential and contains many distinct binding sites to accommodate non-hub proteins.
The problem with understanding a protein-protein network is how one specific hub protein can bind to so many non-hub partners. In certain cases, a change of external environment such as other binding events, partner concentration, pH, ionic strength and temperature can lead to a shift in structural ensemble. But these changes are not capable of accommodating up to hundreds of proteins binding to the same hub.
A new approach in understanding protein-protein interaction is to consider proteins as gene products. Proteins are gene products with different amino acid sequence. A specific set of genes or related genes can have multiple distinct sequences, structures and interactions. Each distinct sequence leads to a distinct structure/conformation. The differences among the conformations may be small, but one gene product can interact with many preferred partners. An example is where a pre-mRNA with four exons and three introns can produce three different mRNAs via exon skipping. This correspond to three gene product with three different protein structure with only minor difference in sequence.
There are several cellular mechanisms that can result in different gene products with many conformations. In alternative splicing, the combinations of exons could result in 38,016 isoforms – different forms of the same protein. All of these isoforms can have different protein-protein interaction due to conformational variability although they are considered the same protein. In cancer, p53 is a tumor suppressor protein encoded by TP53 gene. The isoforms of p53 have many cellular functions. A mutation in TP53 creates multiple gene products of p53, which causes cancer. These p53 variants can regulate hundreds of genes and proteins.
The conclusion is that, although a node in a network is one protein, but the same protein can have multiple gene products with many conformations. Each node of the same protein can be slightly difference in sequence with distinct three-dimensional structure. These differences allows a node to bind with hundreds of partners are different time and perform many essential biological functions.
The network approach helps determine the role of a specific amino acid at a known position in the protein structure. Networks simplify complex system behaviors by splitting the system into a series of links. Links represent the neighboring positions of amino acids in protein molecules. Because proteins are linked in this way and protein structure networks are connected to each other by only a few other amino acid elements, we can determine folding probability. Proteins with denser protein structure networks fold more easily and the folding probability increases as the protein structure becomes more compact.
The network approach can also be applied to the prediction of active centers in proteins. Active centers are protein segments that play key parts in the catalytic reaction of the enzyme function shown by their respective proteins. Scientists have used long-range network topology to create a network skeletons from which they can study only side chains which are essential in the flow of information for the whole protein. Network analysis has showed that active centers occupy a central position in protein structure networks, usually have many neighbors, give unique linkages in their neighborhood, integrate communication for the entire network, do not take part in wasteful actions of ordinary residues, and collect and coordinate most of the energy in the network.
- HOT SPOTS – Essential amino acid deposits of protein-binding sites that have a particularly high binding free energy. Can cluster to form densely packed ‘hot regions’.
- ACTIVE CENTRE – Protein segment that plays a key part in the catalytic reaction of the enzyme function shown by the respective protein.
- BINDING SITE – Amino acid side chains located at the binding interface.
- CENTRAL RESIDUES – Contain catalytic residues (active centres) in addition to binding sites and hit spots.
- CREATIVE ELEMENTS: Least specialized and best among all network elements to live a separated life away from the rest of the network. This is why they continuously chage their contacts. They must connect to elements that are not directly connected to each other so that they do not create a large cumulative disorder that can lead to permanent change.
- Chung-Jung Tasi, Buyong Ma and Ruth Nussinov, Center for Cancer Research Nanobiology Program, SAIC-Frederick, Inc., NCI-Frederick, Frederick, MD 21702, USA.
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