Structural basis of O-GlcNAc recognition by mammalian 14-3-3 proteins

Toleman, Clifford A.; Schumacher, Maria A.; Yu, Seok‐Ho; Zhang, Wenjie; Cox, Nathan J.; Smith, Timothy J.; Soderblom, Erik J.; Wands, Amberlyn M.; Kohler, Jennifer J.; Boyce, Michael

doi:10.1073/pnas.1722437115

Cited by 51 publications

(51 citation statements)

References 77 publications

(72 reference statements)

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“…There are hundreds of known PTMs (Lee and Wu 2015), including phosphorylation, ubiquitination, acetylation, and glycosylation (Baraka-Vidot et al 2015), which are involved in cell division and apoptosis (Zamaraev et al 2017), autophagy (Wani et al 2015), the regulation of cell cycle (Eifler and Vertegaal 2015), energy metabolism (Stram and Payne 2016), and many other cellular processes. The purposes of other less common PTMs, such as SUMOylation (Eifler and Vertegaal 2015), O-GlcNAc monoglycosylation (Toleman et al 2018), and ADP-ribosylation (Luscher et al 2018), are also now being reported. To date, most studies of the PTMs of HSA have been of oxidation, saccharification, nitrosylation, C-or N-terminal truncation, or the conversion of cysteine to dehydroalanine (DHA) (Naldi et al 2017).…”

Section: The Potential Mechanisms Of Impairments In Albumin Functionmentioning

confidence: 99%

Impaired albumin function: a novel potential indicator for liver function damage?

et al. 2019

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Albumin is the most abundant plasma protein and albumin infusion is commonly used. Conventionally, the biologic and therapeutic effects of albumin have been thought to be due to its oncotic properties. However, albumin has a variety of biologic functions, including molecular transport, anti-oxidation, anti-inflammation, endothelial stabilisation, anti-thrombotic effects, and the adjustment of capillary permeability. Despite this, the functions of albumin have not been thoroughly investigated. Recent studies have shown non-alcoholic fatty liver disease (NAFLD), viral hepatitis, cirrhosis, and liver failure to be associated with impairments in albumin function, which are associated with impairments in liver function and disease prognosis. Post-translational modifications of albumin cause structural modifications that affect protein function. Recently, the concentration of albumin associated with normal function, the 'efficient albumin concentration', has been attracting more interest. In addition, although many biologic markers, including albumin concentration, are widely used for the assessment of early liver dysfunction in patients with liver diseases, the predictive values are unsatisfactory. However, clinical evidence has suggested that albumin function may represent a novel biomarker of early impairment in liver function. In this review, we summarise the factors affecting albumin function and discuss the clinical significance of impairments in albumin function in various liver diseases. KEY MESSAGES1. The importance of albumin depends not only on its concentration, but also on its various physiological functions. 2. Impaired albumin function has been reported in a variety of liver diseases, and is associated with disease severity and prognosis, thereby proposing the concept of 'effective albumin concentration'. 3. Albumin dysfunction occurs earlier than other conventional indicators, and albumin dysfunction may be a new biomarker of early impairment in liver function. 4. Many exogenous and endogenous factors lead to post-translational modifications of albumin, which alters the three-dimensional structure of albumin, resulting in a decrease in its biological activity.

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Section: The Potential Mechanisms Of Impairments In Albumin Functionmentioning

confidence: 99%

Impaired albumin function: a novel potential indicator for liver function damage?

et al. 2019

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“…Structural analysis revealed that O-GlcNAcylated peptides bind to 14-3-3 γ proteins in the same amphipathic groove as phosphorylated peptides. Mutagenesis demonstrated that Asp178 and Val181 are critical for binding to O-GlcNAcylated peptides [259].…”

Section: : In Vivo Insight Into the Impact Of O-glcnac On Proteinmentioning

confidence: 99%

Critical observations that shaped our understanding of the function(s) of intracellular glycosylation (O‐GlcNAc)

Zachara

2018

FEBS Letters

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Almost 100 years after the first descriptions of proteins conjugated to carbohydrates (mucins), several studies suggested that glycoproteins were not restricted to the serum, extracellular matrix, cell surface, or endomembrane system. In the 1980’s, key data emerged demonstrating that intracellular proteins were modified by monosaccharides of O-linked β-N-acetylglucosamine (O-GlcNAc). Subsequently, this modification was identified on thousands of proteins that regulate cellular processes as diverse as protein aggregation, localization, post-translational modifications, activity, and interactions. In this Review, we will highlight critical discoveries that shaped our understanding of the molecular events underpinning the impact of O-GlcNAc on protein function, the role that O-GlcNAc plays in maintaining cellular homeostasis, and our understanding of the mechanisms that regulate O-GlcNAc-cycling.

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“…The PPI of 14-3-3 with the carbohydrate-response element-binding protein (ChREBP) regulates transcription of glucose-responsive genes. Whereas most of the 14-3-3 clients require to be phosphorylated prior to 14-3-3 binding 19 , 20 , ChREBP is one of the very few phosphorylation-independent 14-3-3 partner proteins 21 – 23 and interacts with 14-3-3 in a unique α-helical conformation (residues 117–137) 24 . A free sulfate or phosphate in the 14-3-3 phospho-accepting pocket interacts with both proteins 24 .…”

Section: Introductionmentioning

confidence: 99%

Structure-based evolution of a promiscuous inhibitor to a selective stabilizer of protein–protein interactions

et al. 2020

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The systematic stabilization of protein-protein interactions (PPI) has great potential as innovative drug discovery strategy to target novel and hard-to-drug protein classes. The current lack of chemical starting points and focused screening opportunities limits the identification of small molecule stabilizers that engage two proteins simultaneously. Starting from our previously described virtual screening strategy to identify inhibitors of 14-3-3 proteins, we report a conceptual molecular docking approach providing concrete entries for discovery and rational optimization of stabilizers for the interaction of 14-3-3 with the carbohydrate-response element-binding protein (ChREBP). X-ray crystallography reveals a distinct difference in the binding modes between weak and general inhibitors of 14-3-3 complexes and a specific, potent stabilizer of the 14-3-3/ChREBP complex. Structure-guided stabilizer optimization results in selective, up to 26-fold enhancement of the 14-3-3/ChREBP interaction. This study demonstrates the potential of rational design approaches for the development of selective PPI stabilizers starting from weak, promiscuous PPI inhibitors.

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Structural basis of O-GlcNAc recognition by mammalian 14-3-3 proteins

Cited by 51 publications

References 77 publications

Impaired albumin function: a novel potential indicator for liver function damage?

Impaired albumin function: a novel potential indicator for liver function damage?

Critical observations that shaped our understanding of the function(s) of intracellular glycosylation (O‐GlcNAc)

Structure-based evolution of a promiscuous inhibitor to a selective stabilizer of protein–protein interactions

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