5NLJ

Crystal structure of Zn3-E16V human ubiquitin (hUb) mutant adduct, from a solution 70 mM zinc acetate/20% v/v TFE/1.3 mM E16V hUb

Summary for 5NLJ

• Entry DOI: 10.2210/pdb5nlj/pdb
• Related: 3EHV 4K7S 4K7U 4K7W
• Descriptor: Polyubiquitin-B, ACETATE ION, ZINC ION, ... (7 entities in total)
• Functional Keywords: e16v mutant, ligase, ubiquitination, proteasome degradation, signaling protein
• Biological source: Homo sapiens (Human)
• Cellular location: Ubiquitin: Cytoplasm : P0CG47
• Total number of polymer chains: 3
• Total formula weight: 26851.72

Authors

Fermani, S.,Falini, G. (deposition date: 2017-04-04, release date: 2017-04-26, Last modification date: 2024-01-17)

Primary citation

Fermani, S.,Calvaresi, M.,Mangini, V.,Falini, G.,Bottoni, A.,Natile, G.,Arnesano, F.
Aggregation Pathways of Native-Like Ubiquitin Promoted by Single-Point Mutation, Metal Ion Concentration, and Dielectric Constant of the Medium.
Chemistry, 24:4140-4148, 2018

PubMed Abstract: Ubiquitin-positive protein aggregates are biomarkers of neurodegeneration, but the molecular mechanism responsible for their formation and accumulation is still unclear. Possible aggregation pathways of human ubiquitin (hUb) promoted by both intrinsic and extrinsic factors, are here investigated. By a computational analysis, two different hUb dimers are indicated as possible precursors of amyloid-like structures, but their formation is disfavored by an electrostatic repulsion involving Glu16 and other carboxylate residues present at the dimer interface. Experimental data on the E16V mutant of hUb shows that this single-point mutation, although not affecting the overall protein conformation, promotes protein aggregation. It is sufficient to shift the same mutation by only two residues (E18V) to regain the behavior of wild-type hUb. The neutralization of Glu16 negative charge by a metal ion and a decrease of the dielectric constant of the medium by addition of trifluoroethanol (TFE), also promote hUb aggregation. The outcomes of this research have important implications for the prediction of physiological parameters that favor aggregate formation.

PubMed: 29266436
DOI: 10.1002/chem.201705543

Experimental method

X-RAY DIFFRACTION (1.53 Å)