Evolution of oligomeric state through geometric coupling of protein interfaces

Abstract

Oligomerization plays an important role in the function of many proteins. Thus, understanding, predicting, and, ultimately, engi-neering oligomerization presents a long-standing interest. From the perspective of structural biology, protein-protein interactions have mainly been analyzed in terms of the biophysical nature and evolution of protein interfaces. Here, our aim is to quantify the importance of the larger structural context of protein interfaces in protein interaction evolution. Specifically, we ask to what extent intersubunit geometry affects oligomerization state. We define a set of structural parameters describing the overall geometry and relative positions of interfaces of homomeric complexes with different oligomeric states. This allows us to quantify the contribution of direct sequence changes in interfaces versus indirect changes outside the interface that affect intersubunit geometry. We find that such indirect, or allosteric mutations affecting intersubunit geometry via indirect mechanisms are as important as interface sequence changes for evolution of oligomeric states.protein complex evolution | homomeric complexes | protein geometry D uring the course of evolution proteins are constrained by their stability, biochemical activity, and regulation. A specific level of evolutionary constraint is added by interactions with other proteins as a greater proportion of protein structure is involved in its function (1). The basic principles of protein recognition and interface formation have been understood for many years (2), and it has been clear for a long time that considerable differences exist between two functionally distinguishable groups-obligate and transient interfaces (3-5). The evolution of protein interfaces has been related to these two groups as well as other biophysical principles. For instance, Mintseris and Weng have, by appropriately grouping types of protein complexes, shown that protein interfaces are slightly more conserved than the surface but much less than the protein core (6). This makes sense in the light of the prediction where, on average, just two substitutions are sufficient to convert a patch on a protein surface into a protein interface (7). This in turn supports work on so-called hot spot (8-10) and anchor residues (11) or conserved residue clusters (12) in protein interfaces. The shared idea in all of these publications, that there are a few key interface residues, is in agreement with the nature of protein interface packing. Residues on the interface rim, which have more conformational freedom, can accommodate sequence changes more easily than ones in the interface core. More recently, there have been contributions to the field showing how interfaces can evolve through insertions of multiple residues forming so-called enabling loops (13,14).Interactions put additional constraints on protein sequences (15); however, in complexes where a subunit has multiple distinct surface regions that form interfaces (16), we would not expect the increase in evolutionary constraint ...

Archaeal actin from a hyperthermophile forms a single-stranded filament

“…1D) show rotations of similar magnitude. The multiplicity of these interfaces may simply reflect the fact that the main driving force in protein oligomerization and polymerization is burying surface area (43,44), which allows for a good deal of promiscuity.…”

Surface-Induced Dissociation of Homotetramers with D2 Symmetry Yields their Assembly Pathways and Characterizes the Effect of Ligand Binding

“…Previous studies highlight that analysis of the interfaces within oligomers is critical to gaining insight into their assembly pathways (Perica et al, 2012) and that the solution disassembly pathway mimics the assembly pathway (Levy et al, 2008). While several strategies exist through which the dissociation patterns of homomers can be studied by mass spectrometry, they usually require multiple steps that involve solution perturbation and subsequent gasphase dissociation and detection.…”

The Active Form of E6-associated protein (E6AP)/UBE3A Ubiquitin Ligase Is an Oligomer

“…1 and Table 2). Collectively, these features are characteristic of protein-protein binding interfaces rather than crystal packing interactions (67,68). Moreover, the separation distance between N-terminal residues of the Hect domain subunits suggests that the N-terminal targeting domains of the subunits present on the full-length molecule would not hinder trimer formation (Fig.…”

“…Identification of Additional Subunit Interface Residues Affecting E6AP Catalytic Activity-The present data and recent insights into the properties of protein subunit interfaces support the E6AP trimer as the catalytically relevant structure (67,68). The interaction surfaces of the trimer were analyzed by PISA to define other side chain interactions contributing to stability beyond that of Phe 727 (supplemental Table 1).…”