Unraveling the Sugary Code: N-Glycosylation's Impact on Protein Conformation and its Link to Disease

In the intricate dance of cellular processes, a seemingly modest tweak known as N-glycosylation takes center stage. This post-translational modification endows proteins with a sophisticated sugar code, dictating their conformation, assembly, and, crucially, their roles in various diseases.
Published in Cancer, Microbiology, and Neuroscience
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N-Glycosylation as a Modulator of Protein Conformation and Assembly in Disease

Glycosylation, a prevalent post-translational modification, plays a pivotal role in regulating intricate cellular processes by covalently attaching glycans to macromolecules. Dysregulated glycosylation is linked to a spectrum of diseases, encompassing cancer, neurodegenerative disorders, congenital disorders, infections, and inflammation. This review delves into the intricate interplay between glycosylation and protein conformation, with a specific focus on the profound impact of N-glycans on the selection of distinct protein conformations characterized by distinct interactomes—namely, protein assemblies—under normal and pathological conditions across various diseases. We begin by examining the spike protein of the SARS virus, illustrating how N-glycans regulate the infectivity of pathogenic agents. Subsequently, we utilize the prion protein and the chaperone glucose-regulated protein 94 as examples, exploring instances where N-glycosylation transforms physiological protein structures into disease-associated forms. Unraveling these connections provides valuable insights into potential therapeutic avenues and a deeper comprehension of the molecular intricacies that underlie disease conditions. This exploration of glycosylation’s influence on protein conformation effectively bridges the gap between the glycome and disease, offering a comprehensive perspective on the therapeutic implications of targeting conformational mutants and their pathologic assemblies in various diseases. The goal is to unravel the nuances of these post-translational modifications, shedding light on how they contribute to the intricate interplay between protein conformation, assembly, and disease.

 Title: Unraveling the Sugary Code: N-Glycosylation's Impact on Protein Conformation and its Link to Disease

Introduction: In the intricate dance of cellular processes, a seemingly modest tweak known as N-glycosylation takes center stage. This post-translational modification endows proteins with a sophisticated sugar code, dictating their conformation, assembly, and, crucially, their roles in various diseases. A recent review article by Pasala and colleagues delves into the intricate connections among N-glycosylation, protein conformation, and diseases ranging from cancer to neurodegenerative disorders and infections.

Exploring N-Glycosylation and Protein Conformation: Pasala and colleagues' review offers a comprehensive exploration, casting a spotlight on the delicate interplay between N-glycosylation and protein conformation. By unraveling the dynamic relationship between glycans and proteins, the review homes in on how N-glycans choreograph distinct protein conformations in both normal and pathological conditions across a spectrum of diseases, including cancer, neurodegenerative disorders, and infectious diseases.

What Sets This Review Apart: Distinguishing itself from generic overviews, this review plunges into specific examples such as the SARS virus spike protein, the prion protein, and the chaperone glucose-regulated protein 94 (GRP94). Through these vivid examples, it paints a compelling picture of how N-glycosylation reshapes physiological protein structures into disease-associated forms. The review goes beyond surface-level examinations, providing meticulous analyses of glycan-protein interactions and their far-reaching consequences.

Unveiling Therapeutic Avenues: This review emphasizes a paradigm shift in therapeutic strategies by targeting glycosylation-induced conformational mutants. These mutants, characterized by altered three-dimensional structures or conformational dynamics compared to wild-type proteins, emerge as unique and actionable targets for intervention. Notably, the focus extends beyond individual proteins, illuminating how glycan-mediated remodeling influences the entire protein interactome, reshaping functional pathways at a systemic level. This intricate interplay, occurring at both molecular and systems levels, contributes to the profound reshaping of cellular phenotypes.

Conclusion: In essence, this review not only spotlights N-glycosylation as a source of actionable targets for precision therapies but also underscores the transformative potential of modulating glycan-regulated protein structures and functions within a systemic context. As we navigate the sweet complexities of the cellular world, the implications of this sugary code extend far beyond individual proteins, offering a new frontier for innovative approaches to tackle complex diseases.

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Glycosylation
Life Sciences > Biological Sciences > Cell Biology > Post-translational Modifications > Glycosylation
Cancer Biology
Life Sciences > Biological Sciences > Cancer Biology
Neurodegenerative diseases
Life Sciences > Biological Sciences > Neuroscience > Neurological Disorders > Neurodegenerative diseases
SARS-CoV-2
Life Sciences > Biological Sciences > Microbiology > Virology > Virus > SARS Virus > SARS-CoV-2
Prion diseases
Life Sciences > Biological Sciences > Neuroscience > Neurological Disorders > Prion diseases
Chaperones
Life Sciences > Biological Sciences > Cell Biology > Protein Folding > Chaperones