Modularity of the hydrophobic core and evolution of functional diversity in fold A glycosyltransferases

Venkat, Aarya; Tehrani, Daniel; Taujale, Rahil; Yeung, Wayland; Gravel, Nathan; Moremen, Kelley W.; Kannan, Natarajan

doi:10.1016/j.jbc.2022.102212

Cited by 6 publications

(2 citation statements)

References 65 publications

(101 reference statements)

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“…Although we were unsuccessful in determining a donor or acceptor-bound X-ray structure, we were able to identify crucial residues using sequence conservation information by mining over half a million GT-A fold sequences and comparing them to those in the GT92 family. The majority of GT-As that are inverting enzymes utilize Asp or Glu within a conserved xED motif as the catalytic base 36 . In contrast, our bioinformatics and docking data led to the hypothesis, and biochemical analyses confirmed, that H414 functions as the catalytic base in GalS1.…”

Section: Discussionmentioning

confidence: 99%

Structural and biochemical insight into a modular β-1,4-galactan synthase in plants

et al. 2023

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Rhamnogalacturonan I (RGI) is a structurally complex pectic polysaccharide with a backbone of alternating rhamnose and galacturonic acid residues substituted with arabinan and galactan side chains. Galactan synthase 1 (GalS1), transfers galactose and arabinose to either extend or cap the β-1,4 galactan side chains of RGI, respectively. Here we report the structure of GalS1 from Populus trichocarpa, showing a modular protein consisting of an N-terminal domain that represents the founding member of a new family of carbohydrate-binding module, CBMXX (number denoted as 'XX" assigned upon publication), and a C-terminal glycosyltransferase family 92 (GT92) catalytic domain that adopts a GT-A fold. GalS1 exists as a dimer in vitro, with stem domains interacting across the chains in a 'handshake' orientation that is essential for maintaining stability and activity. In addition to understanding the enzymatic mechanism of GalS1, we gained insight into the donor and acceptor substrate binding sites using deep evolutionary analysis, molecular simulations, and biochemical studies. Combining all the results, a mechanism for GalS1 catalysis and a new model for pectic galactan side chain addition are proposed.

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Section: Discussionmentioning

confidence: 99%

Structural and biochemical insight into a modular β-1,4-galactan synthase in plants

et al. 2023

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“…These enzymes are classified into distinct categories, GT-A and GT-B, based on the specific glycosidic bonds they form. GT-A enzymes exhibit a defined structure characterised by a metal-coordinating DxD motif, while GT-B enzymes possess a more flexible structure [4], allowing them to accommodate various sugar substrates. Given the multifaceted roles of GTs in cellular and metabolic processes, including protein folding, stability, cell-cell adhesion, signalling and adaptive immune responses, malfunctions or mutations in GTs have been linked to a spectrum of diseases [5,6].…”

Section: Introductionmentioning

confidence: 99%

Mutations in Glycosyltransferases and Glycosidases: Implications for Associated Diseases

Gu,

Kovacs,

Myung

et al. 2024

Biomolecules

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Glycosylation, a crucial and the most common post-translational modification, coordinates a multitude of biological functions through the attachment of glycans to proteins and lipids. This process, predominantly governed by glycosyltransferases (GTs) and glycoside hydrolases (GHs), decides not only biomolecular functionality but also protein stability and solubility. Mutations in these enzymes have been implicated in a spectrum of diseases, prompting critical research into the structural and functional consequences of such genetic variations. This study compiles an extensive dataset from ClinVar and UniProt, providing a nuanced analysis of 2603 variants within 343 GT and GH genes. We conduct thorough MTR score analyses for the proteins with the most documented variants using MTR3D-AF2 via AlphaFold2 (AlphaFold v2.2.4) predicted protein structure, with the analyses indicating that pathogenic mutations frequently correlate with Beta Bridge secondary structures. Further, the calculation of the solvent accessibility score and variant visualisation show that pathogenic mutations exhibit reduced solvent accessibility, suggesting the mutated residues are likely buried and their localisation is within protein cores. We also find that pathogenic variants are often found proximal to active and binding sites, which may interfere with substrate interactions. We also incorporate computational predictions to assess the impact of these mutations on protein function, utilising tools such as mCSM to predict the destabilisation effect of variants. By identifying these critical regions that are prone to disease-associated mutations, our study opens avenues for designing small molecules or biologics that can modulate enzyme function or compensate for the loss of stability due to these mutations.

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Utilization of glycosyltransferases as a seamless tool for synthesis and modification of the oligosaccharides-A review

Ali

Liaqat

Khazi

et al. 2023

International Journal of Biological Macromolecules

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Modularity of the hydrophobic core and evolution of functional diversity in fold A glycosyltransferases

Cited by 6 publications

References 65 publications

Structural and biochemical insight into a modular β-1,4-galactan synthase in plants

Structural and biochemical insight into a modular β-1,4-galactan synthase in plants

Mutations in Glycosyltransferases and Glycosidases: Implications for Associated Diseases

Utilization of glycosyltransferases as a seamless tool for synthesis and modification of the oligosaccharides-A review

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