Ebook Protein-Protein Interactions
The subject of protein-protein interactions represents a vast ensemble of results from biological, biochemical and biophysical studies carried out to date and cannot be treated in its entirety in any reasonable fashion. The following chapter will focus therefore on particular aspects of protein-protein interactions. It will begin with an overview of some classes of protein-protein interactions and their structural motifs, concentrating on a few important examples of homo- and hetero-oligomers. Next, biophysical methodologies for characterizing protein-protein interactions will be discussed in terms of their advantages and disadvantages for this particular application. Finally, some considerations about the energetics of protein-protein interactions and the coupling of ligand binding with protein association reactions will be presented.
Protein-protein interactions are operative at almost every level of cell function, in the structure of sub-cellular organelles, the transport machinery across the various biological membranes, packaging of chromatin, the network of sub-membrane filaments, musclecontraction, and signal transduction, regulation of gene expression, to name a few. Aberrant protein-protein interactions have implicated in a number of neurological disorders such as Creutzfeld-Jacob and Alzheimer's disease. We will be concerned mainly in this chapter withthe biophysical aspects of the finely tuned specific interactions between proteins involved in the regulation of cell function, namely those proteins implicated in signal transduction and transcriptional regulation.
Because of their importance in development and disease, these systems have been the object of intense research for many years. It has emerged from these studies that nature has employed in many instances a strategy of mixing and matching of domains that specify particular classes of protein-protein interactions, modifying the amino acid sequence in order to confer specificity for particular target proteins. The regulation of cell function brought about by the interactions of these proteins is delicately balanced by the relative affinities of the various protein partners and the modulation of these affinities by the binding of ligands, other proteins, nucleic acids, ions such as Ca2+, and covalent modification, such as specific phosphorlyation or acetylation reactions.
Specificity and the strength of signal transduction is encoded by the exact amino acid sequence of the domain, and it is this relationship between sequence, structure, dynamics, energetics and function that constitutes the fundamental issue for the biophysics of protein-protein interactions. This endeavor therefore requires a structural characterization of the domains and if possible their dispositions within the complete protein and their complexes with their specific protein partners. In addition to a structural characterization, understanding the basis for specificity in these systems necessitates very careful and thorough comparative studies of similar interacting partners or mutated domains in order to bring to light the energetic properties linked to a particular sequence/structure. We must bear in mind that differences as small as 1 kcal/mol in interaction energy between pairs of protein partners can lead to profound differences in cell growth and development.
Posted in :
