5w46
From Proteopedia
Structure of S65D Phosphomimetic Ubiquitin Refined at 1.2 Angstroms Resolution
Structural highlights
FunctionUBB_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 PubMedThe covalent attachment of ubiquitin (Ub) or Ub chains to cellular proteins is a versatile post-translational modification involved in a variety of eukaryotic cellular events. Recently, the post-translational modification of Ub itself by phosphorylation has emerged as an important component of the Ub-signaling system. Specifically, Ub phosphorylation at serine-65 was shown to activate parkin-mediated mitochondrial quality control. However, the impact of phosphorylation on Ub structure and interactions is poorly understood. Here we investigate the recently reported structural changes in Ub upon serine-65 phosphorylation, namely, the equilibrium between a native-like and a novel, alternate conformer of phosphorylated Ub (pUb). We show that this equilibrium is pH-dependent, and the two pUb conformers are linked to the different charge states of the phosphate group. We examined pUb binding to a known Ub-receptor and found that the alternate conformer is binding incompetent. Furthermore, serine-65 phosphorylation affects the conformational equilibrium of K48-linked Ub dimers. Lastly, our crystal structure of S65D Ub and NMR data indicate that phosphomimetic mutations do not adequately reproduce the salient features of pUb. Our results suggest that the pH-dependence of the conformations and binding properties of phosphorylated Ub and polyUb could provide an additional level of modulation in Ub-mediated signaling. Impact of different ionization states of phosphorylated Serine-65 on ubiquitin structure and interactions.,Kazansky Y, Lai MY, Singh RK, Fushman D Sci Rep. 2018 Feb 8;8(1):2651. doi: 10.1038/s41598-018-20860-w. PMID:29422536[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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