A molecular switch orchestrates enzyme specificity and secretory granule morphology

Ji, Suena; Samara, N.L.; Revoredo, Leslie; Zhang, Liping; Tran, Duy T.; Muirhead, Kayla; Tabak, Lawrence A.; Hagen, Karl S.

doi:10.1038/s41467-018-05978-9

Cited by 42 publications

(57 citation statements)

References 71 publications

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“…Four ORFs (Genbank ID of XP_006462966: 361 amino acids, XP_006459007: 414 amino acids, XP_006459008: 274 amino acids, and XP_006458911: 423 amino acids) encode proteins that contain the Ricin B-like lectin fold at either their N-or C-terminal. Proteins that contain a lectin domain are called chimerolectin [29] and occur commonly, for example, the Ricin B-like lectin domain of the fungal Marasmius oreades [30] and the C-domain of the fruit fly Drosophila melanogaster lectin [31].…”

Section: Lectins and Lectin-like Protein In A Bisporusmentioning

confidence: 99%

“…Hence, ABL can display multivalent sugar-binding, and thereby agglutination. Each of the two sugar-binding sites in the ABL monomer is unique because each can distinguish two ligands differing only in the orientation of one hydroxyl group (epimer) [31]. The structure was obtained from the Protein Databank and the three-dimensional structure figure was prepared using PyMoL [44].…”

Section: Structure and Possible Function In The Mushroommentioning

confidence: 99%

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Lectins from the Edible Mushroom Agaricus bisporus and Their Therapeutic Potentials

Ismaya¹,

Tjandrawinata²,

Rachmawati

2020

Molecules

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The mushroom Agaricus bisporus secretes biologically active compounds and proteins with benefits for human health. Most reported proteins from A. bisporus are tyrosinases and lectins. Lectins are of therapeutic or pharmaceutical interest. To date, only limited information is available on A. bisporus lectins and lectin-like proteins. No therapeutic products derived from A. bisporus lectin (ABL) are available on the market despite its extensive exploration. Recently, A. bisporus mannose-binding protein (Abmb) was discovered. Its discovery enriches the information and increases the interest in proteins with therapeutic potential from this mushroom. Furthermore, the A. bisporus genome reveals the possible occurrence of other lectins in this mushroom that may also have therapeutic potential. Most of these putative lectins belong to the same lectin groups as ABL and Abmb. Their relationship is discussed. Particular attention is addressed to ABL and Abmb, which have been explored for their potential in medicinal or pharmaceutical applications. ABL and Abmb have anti-proliferative activities toward cancer cells and a stimulatory effect on the immune system. Possible scenarios for their use in therapy and modification are also presented.

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Section: Lectins and Lectin-like Protein In A Bisporusmentioning

confidence: 99%

Section: Structure and Possible Function In The Mushroommentioning

confidence: 99%

Lectins from the Edible Mushroom Agaricus bisporus and Their Therapeutic Potentials

Ismaya¹,

Tjandrawinata²,

Rachmawati

2020

Molecules

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“…These mechanisms can likely differentiate between GalNAc-T isozymes. Most important is the concerted actions of both the catalytic domain, responsible for addition of GalNAc to S/T residues, and the lectin domain, involved in carbohydrate and peptide binding during follow-up and initial glycosylation respectively (Ten Hagen et al 2003;Fritz et al 2004;Wandall et al 2007;Ji et al 2018). A dynamic interplay between both domains has been observed during initiation of clustered glycosylation (Raman et al 2008;Gerken et al 2011;Lira-Navarrete et al 2015).…”

Section: Introductionmentioning

confidence: 99%

IgA1 hinge-region clustered glycan fidelity is established early during semi-ordered glycosylation by GalNAc-T2

et al. 2019

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GalNAc-type O-glycans are often added to proteins post-translationally in a clustered manner in repeat regions of proteins, such as mucins and IgA1. Observed IgA1 glycosylation patterns show that glycans occur at similar sites with similar structures. It is not clear how the sites and number of glycans added to IgA1, or other proteins, can follow a conservative process. GalNActransferases initiate GalNAc-type glycosylation. In IgA nephropathy, an autoimmune disease, the sites and O-glycan structures of IgA1 hinge-region are altered, giving rise to a glycan autoantigen. To better understand how GalNAc-transferases determine sites and densities of clustered O-glycans, we used IgA1 hinge-region (HR) segment as a probe. Using LC-MS, we demonstrated a semi-ordered process of glycosylation by GalNAc-T2 towards the IgA1 HR. The catalytic domain was responsible for selection of four initial sites based on amino-acid sequence recognition. Both catalytic and lectin domains were involved in multiple second site-selections, each dependent on initial site-selection. Our data demonstrated that multiple start-sites and follow-up pathways were key to increasing the number of glycans added. The lectin domain predominately enhanced IgA1 HR glycan density by increasing synthesis pathway exploration by GalNAc-T2. Our data indicated a link between site-specific glycan addition and clustered glycan density that defines a mechanism of how conserved clustered O-glycosylation patterns and glycoform populations of IgA1 can be controlled by GalNAc-T2. Together, these findings characterized a correlation between glycosylation pathway diversity and glycosylation density, revealing mechanisms by which a single GalNAc-T isozyme can limit and define glycan heterogeneity in a disease-relevant context.

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“…More recently, cell culture studies have demonstrated that Galnt11 glycosylates members of the low-density lipoprotein receptor (LDLR) family in the linker sequence between LDLR class A (LA) repeats (11) and enhances ligand binding (12). Members of the Galnt family (20 members in mammals and 10 in Drosophila) display unique expression patterns and substrates specificities (6,7,(13)(14)(15)(16). Moreover, studies in model systems have demonstrated roles in diverse biological processes including protease processing, secretion, cell signaling, cell adhesion, and organ growth (7,(17)(18)(19)(20)(21)(22)(23)(24).…”

mentioning

confidence: 99%

Galnt11 regulates kidney function by glycosylating the endocytosis receptor megalin to modulate ligand binding

Tian

Wang

Zhang

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Chronic kidney disease (CKD) affects more than 20 million Americans and ∼10% of the population worldwide. Genome-wide association studies (GWAS) of kidney functional decline have identified genes associated with CKD, but the precise mechanisms by which they influence kidney function remained largely unexplored. Here, we examine the role of 1 GWAS-identified gene by creating mice deficient for Galnt11, which encodes a member of the enzyme family that initiates protein O-glycosylation, an essential posttranslational modification known to influence protein function and stability. We find that Galnt11-deficient mice display low-molecular-weight proteinuria and have specific defects in proximal tubule-mediated resorption of vitamin D binding protein, α1-microglobulin, and retinol binding protein. Moreover, we identify the endocytic receptor megalin (LRP2) as a direct target of Galnt11 in vivo. Megalin in Galnt11-deficient mice displays reduced ligand binding and undergoes age-related loss within the kidney. Differential mass spectrometry revealed specific sites of Galnt11-mediated glycosylation within mouse kidney megalin/LRP2 that are known to be involved in ligand binding, suggesting that O-glycosylation directly influences the ability to bind ligands. In support of this, recombinant megalin containing these sites displayed reduced albumin binding in cells deficient for Galnt11. Our results provide insight into the association between GALNT11 and CKD, and identify a role for Galnt11 in proper kidney function.

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A molecular switch orchestrates enzyme specificity and secretory granule morphology

Cited by 42 publications

References 71 publications

Lectins from the Edible Mushroom Agaricus bisporus and Their Therapeutic Potentials

Lectins from the Edible Mushroom Agaricus bisporus and Their Therapeutic Potentials

IgA1 hinge-region clustered glycan fidelity is established early during semi-ordered glycosylation by GalNAc-T2

Galnt11 regulates kidney function by glycosylating the endocytosis receptor megalin to modulate ligand binding

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