title: Recognition of Poly-Ubiquitins by the Proteasome through Protein Refolding Guided by Electrostatic and Hydrophobic Interactions.
abstract: Specificity of protein degradation by cellular proteasomes comes from tetra-ubiquitin recognition. We carry out molecular dynamics simulations to characterize how the ubiquitin receptor Rpn10 recognizes in the 26S proteasome K48-linked tetra-ubiquitin. In the binding pose, ubiquitin and Rpn10 interact primarily through hydrophobic patches. However, K48-linked tetra-ubiquitin mostly assumes a closed form in solution prior to binding, in which its hydrophobic patches are not exposed to solvent. Likewise, the hydrophobic ubiquitin interacting motifs (UIMs) of Rpn10 are mostly protected prior to binding. As a result, ubiquitin recognition in the proteasome requires refolding of both K48-linked tetra-ubiquitin and Rpn10. Simulations suggest that conserved complementary electrostatic patterns of Rpn10 and ubiquitins guide protein association (stage 1 in the recognition process), which induces refolding (stage 2), and then facilitates formation of hydrophobic contacts (stage 3). The simulations also explain why Rpn10 has a higher affinity for K48-linked tetra-ubiquitin than for mono-ubiquitin and K48-linked di- and tri-ubiquitins. Simulation results expand on the current view that the flexible arm of Rpn10 acts as an extended fragment of α-helices and flexible coils in the recognition process.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Chemistry, University of Texas at El Paso , El Paso, Texas 79968, United States.
authors.forename: Lela
authors.initials: L
authors.lastname: Vuković
authors.forename: Till
authors.initials: T
authors.lastname: Rudack
authors.forename: Wei
authors.initials: W
authors.lastname: Han
authors.forename: Klaus
authors.initials: K
authors.lastname: Schulten
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D058849:Protein Refolding; D016601:RNA-Binding Proteins; D012441:Saccharomyces cerevisiae / Q000737:chemistry* / Q000201:enzymology; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry* / Q000378:metabolism; D012568:Schizosaccharomyces / Q000737:chemistry* / Q000201:enzymology; D029702:Schizosaccharomyces pombe Proteins / Q000737:chemistry* / Q000378:metabolism; D016415:Sequence Alignment; D055672:Static Electricity; D040681:Structural Homology, Protein; D013379:Substrate Specificity; D013816:Thermodynamics; D025801:Ubiquitin / Q000737:chemistry* / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D016601:RNA-Binding Proteins; C122019:RPN10 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D029702:Schizosaccharomyces pombe Proteins; D025801:Ubiquitin; C498507:pus1 protein, S pombe; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease