Modeling and Structure Determination of Homo-Oligomeric Proteins: An Overview of Challenges and Current Approaches

Abstract

Protein homo-oligomerization is a very common phenomenon, and approximately half of proteins form homo-oligomeric assemblies composed of identical subunits. The vast majority of such assemblies possess internal symmetry which can be either exploited to help or poses challenges during structure determination. Moreover, aspects of symmetry are critical in the modeling of protein homo-oligomers either by docking or by homology-based approaches. Here, we first provide a brief overview of the nature of protein homo-oligomerization. Next, we describe how the symmetry of homo-oligomers is addressed by crystallographic and non-crystallographic symmetry operations, and how biologically relevant intermolecular interactions can be deciphered from the ordered array of molecules within protein crystals. Additionally, we describe the most important aspects of protein homo-oligomerization in structure determination by NMR. Finally, we give an overview of approaches aimed at modeling homo-oligomers using computational methods that specifically address their internal symmetry and allow the incorporation of other experimental data as spatial restraints to achieve higher model reliability.

A proteome scale study reveals how plastic surfaces and agitation promote protein aggregation

“…This shows that lateral interactions between proteins on the surface are a key mechanism for adsorption under shear. Homo-oligomers, owing to their stability and lower exposed surfaces 57 , are less prone to such interactions and readily desorbed by the water flow. Therefore, it would be their limited adsorption on the surface under shear that would finally stabilize them upon exposure to combined stresses described here.…”

Higher‐order structure formation using refined monomer structures of lipid raft markers, Stomatin, Prohibitin, Flotillin, and HflK/C‐related proteins

“…Docking methods may be more useful when proper oligomer templates are not available but the monomer structure is reliable [ 12 ]. Several protein–protein docking methods have been reported to date [ 13 ], some of which are available as public web servers for predicting homo‐oligomer structures. The GalaxyHomomer predicts the homo‐oligomer structure from either the amino acid sequence or the monomer structure [ 12 ].…”

Staphylococcus aureus Exfoliative Toxin E, Oligomeric State and Flip of P186: Implications for Its Action Mechanism

“…Figure 6 C shows a structural representation of the homodimer conformation ETE 2 -CP-0. Like the vast majority of protein homodimers in nature, the proposed structure displays C 2 symmetry [ 38 ], i.e., it is symmetric upon 180° rotation with respect to the indicated vertical axis ( Figure 6 C). It is worth noting that the proposed model significantly diverges from the crystallographic homodimers present in the AU of PDB structures: 8DAX and 5C2Z, as confirmed by the different composition of interface residues and heavy atom RMSD values ( Table S4 ).…”