The Center for Biomedical Mass Spectrometry (CBMS) has been awarded a grant by the Massachusetts Life Science Center to advance the ability to characterize spike protein glycosylation as respiratory viruses evolve. The CBMS applies mass spectrometry methods to meet the emerging needs in biomedicine. As part of this award, CBMS has just installed a new Waters SELECT SERIES Cyclic IMS system. The Cyclic system represents a breakthrough technology that will facilitate rapid and accurate characterization of virus spike protein glycosylation to support virus surveillance and vaccine development.
Respiratory viruses including influenza and coronaviruses evolve rapidly as they circulate in the human population. These proteins are coated with a spike protein that recognizes receptors in host airway cells. Spike proteins are decorated by sugar molecules known as glycans. These glycans enhance the structures and functions of proteins, including the virus spike proteins. Researchers track the genetic sequences of viruses as they evolve. The genetic sequences do not predict the manner in which glycans alter the structure and function of virus spike proteins.
New research from the Zaia laboratory has been published in Molecular Proteomics: "Why glycosylation matters in building a better flu vaccine".
Low vaccine efficacy against seasonal influenza A virus (IAV) stems from the ability of the virus to evade existing immunity while maintaining fitness. While most potent neutralizing antibodies bind antigenic sites on the globular head domain of the IAV envelope glycoprotein hemagglutinin (HA), the error-prone IAV polymerase enables rapid evolution of key antigenic sites, resulting in immune escape. Significantly, the appearance of new N-glycosylation consensus sequences (sequons, NXT/NXS, rarely NXC) on the HA globular domain occurs among the more prevalent mutations as an IAV strain undergoes antigenic drift. The appearance of new glycosylation shields underlying amino acid residues from antibody contact, tunes receptor specificity, and balances receptor avidity with virion escape, all of which help maintain viral propagation through seasonal mutations. The determination of site-specific glycosylation of IAV glycoproteins would enable development of vaccines that take advantage of glycosylation-dependent mechanisms whereby virus glycoproteins are processed by antigen presenting cells
Vascular endothelial growth factor receptor 2 (VEGFR2) is a heavily N-glycosylated pro-angiogenic receptor tyrosine kinase. Stimulation of the receptor by vascular endothelial growth factor (VEGF) induces quiescent endothelial cells to proliferate and sprout, and VEGFR2 signaling is also required for tumor growth and metastasis. In a new paper in the Journal of Biological Chemistry by Kevin Brown Chandler and colleagues in the Costello and Rahimi laboratories demonstrated that the glycosylation status of VEGFR2 alters signaling through the receptor. Specifically, sialic acid-capped N-glycans at site N247 oppose ligand-mediated receptor activation, whereas asialo-glycans (lacking sialic acid) favor VEGFR2 activation.
The Henry I. Russek Award Nominating Committee and the Russek Executive Committee would like to announce the winners of this year’s Department of Biochemistry awards. The honorable mention was awarded to Deborah Chang who is a student in Dr. Zaia’s lab, second prize was awarded to Julia Hicks-Berthet who is a student in Dr. Varelas's lab and the first prize was awarded to Elena Stampouloglou, who is a student in Dr. Varelas's lab. There is more great news for our department! The first prize awardee for the Molecular & Translational Medicine program is Rekha Raghunathan, a student in Dr. Zaia’s lab and the first prize awardee for the Genetics & Genomics program is Stefanie Chan, a student in Dr. Perissi’s lab. Congratulations to all of the awardees (and their mentors)!
So, we'll see you all this Friday, April 26th in Hiebert Lounge for Henry I. Russek Student Achievement Day 2019 and the keynote address to be delivered by Dr. Xiowei Zhuang; her talk is entitled “Illuminating Biology at the Nanoscale and Systems Scale by Imaging”.
Catherine Costello, PhD, the William Fairfield Warren Distinguished Professor at Boston University School of Medicine (BUSM), has received the 2019 Lifetime Achievement in Proteomics Award from the U.S. Human Proteome Organization (U.S. HUPO). This inaugural award recognizes a career of discovery that has made a lasting impact in the field of proteomics, the field which explores the distribution, dynamics and modifications of proteins in cells and living organisms and their relationships to health and disease. ... (link)
Dr. Cathy Costello honored with special issue in The Journal of the American Society for Mass Spectrometry
In recognition of Dr. Catherine Costello's 2017 ASMS Award for a Distinguished Contribution in Mass Spectrometry, the entire June 2018 issue focused on Mass Spectrometry in Glycobiology and Related Fields and was a tribute to Dr. Costello's numerous contributions to the field. The first article in this issue written by Joe Zaia and Veronica Bierbaum describes Dr. Costello's vision and leadership in glycoscience mass spectrometry.
Please also read about the current research in the Costello lab.
The Zaia laboratory's recent study: “Software for peak finding and elemental composition assignment for glycosaminoglycan tandem mass spectra” has been selected to appear in a special virtual issue of ASBMB journal content on Omics of lipids, glycans and polar metabolites. This paper was selected from hundreds of papers and best represents the exciting advances made in studying these systems over the last three years.
Glycosaminoglycans (GAGs) covalently linked to proteoglycans are characterized by repeating disaccharide units and variable sulfation patterns along the chain. The Zaia laboratory and others have demonstrated the usefulness of tandem mass spectrometry (MS2) for assigning the structures of GAG saccharides; however, manual interpretation of tandem mass spectra is time-consuming, so computational methods must be employed. The Zaia group developed GAGfinder, the first tandem mass spectrum peak finding algorithm developed specifically for GAGs. GAGfinder is a targeted, brute force approach to spectrum analysis that utilizes precursor composition information to generate all theoretical fragments. GAGfinder also performs peak isotope composition annotation, which is typically a subsequent step for averagine-based methods.
New research papers from the Zaia laboratory have established novel strategies for analyzing glycans and glycopeptides.
Glycomics and glycoproteomics analyses by mass spectrometry require efficient front-end separation methods to enable deep characterization of heterogeneous glycoform populations. Chromatography methods are generally limited in their ability to resolve glycoforms using mobile phases that are compatible with online liquid chromatography-mass spectrometry (LC-MS). The adoption of capillary electrophoresis-mass spectrometry methods (CE-MS) for glycomics and glycoproteomics is limited by the lack of convenient interfaces for coupling the CE devices to mass spectrometers. Here, we describe the application of a microfluidics-based CE-MS system for analysis of released glycans, glycopeptides and monosaccharides. We demonstrate a single CE method for analysis three different modalities, thus contributing to comprehensive glycoproteomics analyses. In addition, we explored compatible sample derivatization methods. We used glycan TMT-labeling to improve electrophoretic migration and enable multiplexed quantitation by tandem MS. We used sialic acid linkage-specific derivatization methods to improve separation and the level of information obtained from a single analytical step. Capillary electrophoresis greatly improved glycoform separation for both released glycans and glycopeptides over that reported for chromatography modes more frequently employed for such analyses. Overall, the CE-MS method described here enables rapid setup and analysis of glycans and glycopeptides using mass spectrometry
To learn more:
- Khatri, K.; Klein, J. A.; Zaia, J. Use of an informed search space maximizes confidence of site-specific assignment of glycoprotein glycosylation. Anal Bioanal Chem 2017, 409, 607-618. Pubmed Link
- Khatri, K.; Klein, J. A.; Haserick, J.; Leon, D. R.; Costello, C. E.; McComb, M. E.; Zaia, J. Microfluidic capillary electrophoresis-mass spectrometry for analysis of monosaccharides, oligosaccharides and glycopeptides. Anal. Chem. 2017, 89, 6645-6655. Pubmed Link
Congratulations to several Biochemistry faculty who were recently awarded Dahoud Breast Cancer Pilot Awards.
Alla Grishok, PhD, Associate Professor of Biochemistry, Dafne Cardamone, PhD, Instructor, and Catherine Costello, PhD, Director of Center for Biomedical Mass Spectrometry, will study regulation of cancer-promoting Myc protein using a model metastatic breast cancer cell line. Myc binds DNA and activates a large network of genes that together transform normal cells into cancer cells. Myc activity is elevated in most human cancers and is especially relevant for Myc-driven triple (estrogen, progesterone and Her2) negative breast cancer. Dr. Grishok and colleagues will investigate new mechanisms that increase Myc protein activity: 1) adding specific sugar residues, and 2) protein truncation. New compounds that directly inhibit Myc or inhibit enzymes that activate Myc could be developed into new cancer therapies.
Xaralabos Varelas, PhD, Associate Professor of Biochemistry and Stefano Monti, PhD, Associate Professor of Medicine and Biostatistics, will study the causes of aggressive triple negative breast cancers. The team will determine how abnormal signaling networks drive gene expression changes that lead to aggressive breast cancers and then categorize subsets of aggressive breast cancers, thereby better targeting the most effective treatments based on the genes expressed in the tumor.
Cathy Costello was recently awarded the 2017 Award for a Distinguished Contribution in Mass Spectrometry by the American Society for Mass Spectrometry. This award recognizes a singular significant achievement and was for her pioneering contributions to the development of tandem mass spectrometry of glycans and glycoconjugates. Addtional details of the award can be found on the ASMS web page. Congratulations Cathy!