title: Critical residue that promotes protein dimerization: a story of partially exposed Phe25 in 14-3-3σ.
abstract: Many proteins exist and function as oligomers. While hydrophobic interactions have been recognized as the major driving force for oligomerization, detailed molecular mechanisms for the assembly are unknown. Here, we used 14-3-3σ as a model protein and investigated the role of hydrophobic residues at the dimeric interface using MD simulations and coimmunoprecipitations. We found that a half-exposed and half-buried residue in the interface, Phe(25), plays a more important role in promoting homodimerization than the hydrophobic core residues by organizing both favorable hydrophobic and hydrophilic interactions. Phe(25) is critical in packing and stabilizing hydrophobic core residues. We conclude that the structural stability of hydrophobic cores is critical for a stable homodimer complex and this stable property can be bestowed by residues outside of hydrophobic core. The important organizing activity of Phe(25) for homodimerization of 14-3-3σ originates from its unique physical location, rigidity, size, and hydrophobicity. Thus, hydrophobic residues that are not deeply buried at the oligomeric interface may play important but different roles from the buried core residues and they may promote oligomerization by organizing co-operativity of core and other residues for favorable hydrophobic and electrostatic interactions.
authors.affiliation: Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States.
authors.forename: Jing-Yuan
authors.initials: JY
authors.lastname: Liu
authors.forename: Zhaomin
authors.initials: Z
authors.lastname: Li
authors.forename: Huian
authors.initials: H
authors.lastname: Li
authors.forename: Jian-Ting
authors.initials: JT
authors.lastname: Zhang
mesh_terms: D048948:14-3-3 Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018360:Crystallography, X-Ray; D005092:Exonucleases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D005095:Exoribonucleases; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D047468:Immunoprecipitation; D056004:Molecular Dynamics Simulation; D009154:Mutation; D010649:Phenylalanine; D055503:Protein Multimerization; D055550:Protein Stability; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D055672:Static Electricity; D013816:Thermodynamics; D014867:Water / Q000737:chemistry
chemical_list: D048948:14-3-3 Proteins; D014408:Biomarkers, Tumor; D014867:Water; D010649:Phenylalanine; D005092:Exonucleases; D005095:Exoribonucleases; C413442:SFN protein, human