Mechanisms of protein oligomerization, the critical role of insertions and deletions in maintaining different oligomeric states

Abstract

The main principles of protein-protein recognition are elucidated by the studies of homooligomers which in turn mediate and regulate gene expression, activity of enzymes, ion channels, receptors, and cell-cell adhesion processes. Here we explore oligomeric states of homologous proteins in various organisms to better understand the functional roles and evolutionary mechanisms of homooligomerization. We observe a great diversity in mechanisms controlling oligomerization and focus in our study on insertions and deletions in homologous proteins and how they enable or disable complex formation. We show that insertions and deletions which differentiate monomers and dimers have a significant tendency to be located on the interaction interfaces and about a quarter of all proteins studied and forty percent of enzymes have regions which mediate or disrupt the formation of oligomers. We suggest that relatively small insertions or deletions may have a profound effect on complex stability and/or specificity. Indeed removal of complex enabling regions from protein structures in many cases resulted in the complete or partial loss of stability. Moreover, we find that insertions and deletions modulating oligomerization have a lower aggregation propensity and contain a larger fraction of polar, charged residues, glycine and proline compared to conventional interfaces and protein surface. Most likely, these regions may mediate specific interactions, prevent nonspecific dysfunctional aggregation and preclude undesired interactions between close paralogs therefore separating their functional pathways. Last, we show how the presence or absence of insertions and deletions on interfaces might be of practical value in annotating protein oligomeric states.homodimer | homooligomer protein | protein structural evolution

Raf Kinase Inhibitor Protein (RKIP) Dimer Formation Controls Its Target Switch from Raf1 to G Protein-coupled Receptor Kinase (GRK) 2

“…Perturbations within the loop structure were detected in NMR studies with a mutant of RKIP, which at least partially imitates a phosphorylation at this site (RKIP S153E ) (14). Further observations by others strengthen our assumption that this loop represents the interface for RKIP dimerization: loops in general often participate in protein-protein interactions (45,46); particularly, loops with a relatively high fraction of polar, charged residues, as well as glycines and prolines have been suggested to be involved in protein dimerization (37,47). Indeed, loop 127-150 contains eight charged and eight polar amino acids, as well as two glycines and two prolines of 24 amino acids; Banfield et al (8) have generated crystals of dimeric hRKIP and suggested this loop as a putative dimer interface.…”

“…They promote conformational changes and alter surface properties of proteins and may thereby affect protein-protein interactions, activation/ inhibition of enzyme activity, or self-association. Self-association of proteins can increase protein stability and generate new binding sites and thus alter protein function (37)(38)(39)(40)(41)(42)(43). Surprisingly, homo-oligomerization as an efficient mechanism to control protein-protein interactions has thus far not been taken into consideration for RKIP.…”

The effect of nanoscale surface curvature on the oligomerization of surface-bound proteins

“…In biomedical products, for example pharmaceutical formulations, chemicals or co-solvents can be added to either stabilize or compete with contacts between proteins [76]. Oligomerization of proteins can also be modified by changing the primary sequence of the protein at specific protein-coupling interfaces [76,77]. These changes will, of course, affect entire protein populations.…”

Function, kinetic properties, crystallization, and regulation of microbial malate dehydrogenase

“…Homo-oligomeric proteins are a source of diversity and structural specificity under intensive study for a better understanding of their functional roles in providing stability and protection against denaturation and for the elucidation of the mechanisms involved in the evolution of structure-function (Hashimoto and Panchenko, 2010). In this regard, the MDH enzyme has been widely used as a model because of its presence in different subcellular compartments and as different functional oligomeric states (dimers or tetramers).…”