5nlj

From Proteopedia

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Revision as of 05:56, 3 January 2018

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

Structural highlights

5nlj is a 3 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , , ,
Related:	4k7s, 4k7u, 4k7w, 3ehv
Gene:	UBB (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[UBB_HUMAN] Ubiquitin exists either covalently attached to another protein, or free (unanchored). When covalently bound, it is conjugated to target proteins via an isopeptide bond either as a monomer (monoubiquitin), a polymer linked via different Lys residues of the ubiquitin (polyubiquitin chains) or a linear polymer linked via the initiator Met of the ubiquitin (linear polyubiquitin chains). Polyubiquitin chains, when attached to a target protein, have different functions depending on the Lys residue of the ubiquitin that is linked: Lys-6-linked may be involved in DNA repair; Lys-11-linked is involved in ERAD (endoplasmic reticulum-associated degradation) and in cell-cycle regulation; Lys-29-linked is involved in lysosomal degradation; Lys-33-linked is involved in kinase modification; Lys-48-linked is involved in protein degradation via the proteasome; Lys-63-linked is involved in endocytosis, DNA-damage responses as well as in signaling processes leading to activation of the transcription factor NF-kappa-B. Linear polymer chains formed via attachment by the initiator Met lead to cell signaling. Ubiquitin is usually conjugated to Lys residues of target proteins, however, in rare cases, conjugation to Cys or Ser residues has been observed. When polyubiquitin is free (unanchored-polyubiquitin), it also has distinct roles, such as in activation of protein kinases, and in signaling.^[1] ^[2]

Publication Abstract from PubMed

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.

Aggregation pathways of native-like ubiquitin promoted by single-point mutation, metal ion concentration and dielectric constant of the medium.,Fermani S, Calvaresi M, Mangini V, Falini G, Bottoni A, Natile G, Arnesano F Chemistry. 2017 Dec 20. doi: 10.1002/chem.201705543. PMID:29266436^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Huang F, Kirkpatrick D, Jiang X, Gygi S, Sorkin A. Differential regulation of EGF receptor internalization and degradation by multiubiquitination within the kinase domain. Mol Cell. 2006 Mar 17;21(6):737-48. PMID:16543144 doi:S1097-2765(06)00120-1
↑ Komander D. The emerging complexity of protein ubiquitination. Biochem Soc Trans. 2009 Oct;37(Pt 5):937-53. doi: 10.1042/BST0370937. PMID:19754430 doi:10.1042/BST0370937
↑ 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. 2017 Dec 20. doi: 10.1002/chem.201705543. PMID:29266436 doi:http://dx.doi.org/10.1002/chem.201705543

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5nlj"

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 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
-Zinc ions bridging two ubiquitin molecules (with His68 at the interface) contribute to select a subset of conformers from the noncovalent dimer ensemble, thus restricting quaternary structure dynamics, which hampers apo-protein crystallization. The type of selected conformer is shown to determine the crystal packing, which varies from orthorhombic to cubic symmetry.
+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.
-Conformational selection of ubiquitin quaternary structures driven by zinc ions.,Fermani S, Falini G, Calvaresi M, Bottoni A, Calo V, Mangini V, Arnesano F, Natile G Chemistry. 2013 Nov 11;19(46):15480-4. doi: 10.1002/chem.201302229. Epub 2013 Oct, 10. PMID:24123543<ref>PMID:24123543</ref>
+Aggregation pathways of native-like ubiquitin promoted by single-point mutation, metal ion concentration and dielectric constant of the medium.,Fermani S, Calvaresi M, Mangini V, Falini G, Bottoni A, Natile G, Arnesano F Chemistry. 2017 Dec 20. doi: 10.1002/chem.201705543. PMID:29266436<ref>PMID:29266436</ref>
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>

5nlj

From Proteopedia

Revision as of 05:56, 3 January 2018

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

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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