Publications by Year: 2020

Mealer RG, Jenkins BG, Chen C-Y, Daly MJ, Ge T, Lehoux S, Marquardt T, Palmer CD, Park JH, Parsons PJ, et al. The schizophrenia risk locus in SLC39A8 alters brain metal transport and plasma glycosylation. Sci Rep. 2020;10 (1) :13162.Abstract
A common missense variant in SLC39A8 is convincingly associated with schizophrenia and several additional phenotypes. Homozygous loss-of-function mutations in SLC39A8 result in undetectable serum manganese (Mn) and a Congenital Disorder of Glycosylation (CDG) due to the exquisite sensitivity of glycosyltransferases to Mn concentration. Here, we identified several Mn-related changes in human carriers of the common SLC39A8 missense allele. Analysis of structural brain MRI scans showed a dose-dependent change in the ratio of T2w to T1w signal in several regions. Comprehensive trace element analysis confirmed a specific reduction of only serum Mn, and plasma protein N-glycome profiling revealed reduced complexity and branching. N-glycome profiling from two individuals with SLC39A8-CDG showed similar but more severe alterations in branching that improved with Mn supplementation, suggesting that the common variant exists on a spectrum of hypofunction with potential for reversibility. Characterizing the functional impact of this variant will enhance our understanding of schizophrenia pathogenesis and identify novel therapeutic targets and biomarkers.
Bi Y, Zimmer J. Structure and Ligand-Binding Properties of the O Antigen ABC Transporter Carbohydrate-Binding Domain. Structure. 2020;28 (2) :252-258.e2.Abstract
A hallmark of Gram-negative bacteria is an asymmetric outer membrane containing lipopolysaccharides (LPSs) in the extracellular leaflet. LPS molecules consist of lipid A, which is connected to the inner and outer core oligosaccharides. This LPS core structure is extended in the periplasm by the O antigen, a variable and serotype-defining polysaccharide. In the ABC transporter-dependent LPS biosynthesis pathway, the WzmWzt transporter secretes the complete O antigen across the inner membrane for ligation to the LPS core. In some O antigen transporters, the nucleotide-binding domain of Wzt is fused C-terminally to a carbohydrate-binding domain (CBD) that interacts with the O antigen chain. Here, we present the crystal structure of the Aquifex aeolicus CBD that reveals a conserved flat and a variable twisted jelly-roll surface. The CBD dimer is stabilized by mutual β strand exchange. Microbial glycan array binding studies with the isolated CBD provide insights into its interaction with complex carbohydrates.
Kelm M, Quiros M, Azcutia V, Boerner K, Cummings RD, Nusrat A, Brazil JC, Parkos CA. Targeting epithelium-expressed sialyl Lewis glycans improves colonic mucosal wound healing and protects against colitis. JCI Insight. 2020;5 (12).Abstract
Dysregulated healing of injured mucosa is a hallmark of many pathological conditions, including inflammatory bowel disease. Mucosal injury and chronic intestinal inflammation are also associated with alterations in epithelial glycosylation. Previous studies have revealed that inflammation-induced glycan sialyl Lewis A on epithelial CD44v6 acts as a ligand for transmigrating PMNs. Here we report that robust sialylated Lewis glycan expression was induced in colonic mucosa from individuals with ulcerative colitis and Crohn disease as well as in the colonic epithelium of mice with colitis induced by dextran sodium sulfate (DSS). Targeting of sialylated epithelial Lewis glycans with mAb GM35 reduced disease activity and improved mucosal integrity during DSS-induced colitis in mice. Wound healing studies revealed increased epithelial proliferation and migration responses as well as improved mucosal repair after ligation of epithelial sialyl Lewis glycans. Finally, we showed that GM35-mediated increases in epithelial proliferation and migration were mediated through activation of kinases that signal downstream of CD44v6 (Src, FAK, Akt). These findings suggest that sialylated Lewis glycans on CD44v6 represent epithelial targets for improved recovery of intestinal barrier function and restitution of mucosal homeostasis after inflammation or injury.
Mehta AY, Heimburg-Molinaro J, Cummings RD. Tools for generating and analyzing glycan microarray data. Beilstein J Org Chem. 2020;16 :2260-2271.Abstract
Glycans are one of the major biological polymers found in the mammalian body. They play a vital role in a number of physiologic and pathologic conditions. Glycan microarrays allow a plethora of information to be obtained on protein-glycan binding interactions. In this review, we describe the intricacies of the generation of glycan microarray data and the experimental methods for studying binding. We highlight the importance of this knowledge before moving on to the data analysis. We then highlight a number of tools for the analysis of glycan microarray data such as data repositories, data visualization and manual analysis tools, automated analysis tools and structural informatics tools.
Luetscher RND, McKitrick TR, Gao C, Mehta AY, McQuillan AM, Kardish R, Boligan KF, Song X, Lu L, Heimburg-Molinaro J, et al. Unique repertoire of anti-carbohydrate antibodies in individual human serum. Sci Rep. 2020;10 (1) :15436.Abstract
Humoral immunity to pathogens and other environmental challenges is paramount to maintain normal health, and individuals lacking or unable to make antibodies are at risk. Recent studies indicate that many human protective antibodies are against carbohydrate antigens; however, little is known about repertoires and individual variation of anti-carbohydrate antibodies in healthy individuals. Here we analyzed anti-carbohydrate antibody repertoires (ACARs) of 105 healthy individual adult donors, aged 20-60 from different ethnic backgrounds to explore variations in antibodies, as defined by binding to glycan microarrays and by affinity purification. Using microarrays that contained > 1,000 glycans, including antigens from animal cells and microbes, we profiled the IgG and IgM ACARs from all donors. Each donor expressed many ACAs, but had a relatively unique ACAR, which included unanticipated antibodies to carbohydrate antigens not well studied, such as chitin oligosaccharides, Forssman-related antigens, globo-type antigens, and bacterial glycans. We also saw some expected antibodies to ABO(H) blood group and α-Gal-type antigens, although these also varied among individuals. Analysis suggests differences in ACARs are associated with ethnicity and age. Thus, each individual ACAR is relatively unique, suggesting that individualized information could be useful in precision medicine for predicting and monitoring immune health and resistance to disease.