This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. T-cell antigens presented by the CD1a antigen-presenting protein isolated from Mycobacterium tuberculosis were studied to determine their structure and requirements for their antigenic presentation by CD1a. BUSM MS Resource efforts included ESI MS and MS/MS and GC/EI MS experiments and data interpretation. The series were found to be lipopeptides, structurally related to the iron-binding mycobactins D. b. Moody et al, Science, 2004). These results defined a new class of CD1 ligands that may have anti-HIV activity. Investigations of the structure/biological activity relationships for this family of molecules are proceeding. When the X-ray structures were completed they supported the proposed basis for the binding specificity that was built on correlations between the determined structures and observed activity. Structure analysis of CD1a co-crystallized with a synthetic mycobactin lipopeptide at 2.8 ? resolution revealed that the single alkyl chain is inserted deep within the A-prime pocket of the groove, whereas its two peptidic branches protrude along the F pocket to the outer, alpha-helical surface of CD1a for recognition by the TCR. Remarkably, the cyclised lysine branch of the peptide moiety lies in the shallow F-prime pocket in a conformation that closely mimics that of the alkyl chain in the CD1a-sulfatide structure. Thus, this structural study illustrated how a single chain lipid can be presented by CD1 and that the peptide moiety of the lipopeptide is recognized by the TCR in contrast to dual chain glycolipids where the carbohydrate head group, as well as portions of the second alkyl chain, provide the basis for TCR specificity. A recent commentary in Nature (DB Moody, Nature. 2007 Jul 5;448(7149):36-7) incorporated concepts developed in the collaborative project. Synthetic versions of the lipopeptide with different stereochemistries have been prepared and their activities have been determnined, showing clearly that the stereochemistry is important for activity. A manuscript describing these results has been submitted and revised for publication in J. Biol. Chem.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
5P41RR010888-13
Application #
7955894
Study Section
Special Emphasis Panel (ZRG1-BCMB-H (40))
Project Start
2009-06-01
Project End
2010-05-31
Budget Start
2009-06-01
Budget End
2010-05-31
Support Year
13
Fiscal Year
2009
Total Cost
$2,475
Indirect Cost
Name
Boston University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Lu, Yanyan; Jiang, Yan; Prokaeva, Tatiana et al. (2017) Oxidative Post-Translational Modifications of an Amyloidogenic Immunoglobulin Light Chain Protein. Int J Mass Spectrom 416:71-79
Sethi, Manveen K; Zaia, Joseph (2017) Extracellular matrix proteomics in schizophrenia and Alzheimer's disease. Anal Bioanal Chem 409:379-394
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Wang, Yun Hwa Walter; Meyer, Rosana D; Bondzie, Philip A et al. (2016) IGPR-1 Is Required for Endothelial Cell-Cell Adhesion and Barrier Function. J Mol Biol 428:5019-5033
Srinivasan, Srimathi; Chitalia, Vipul; Meyer, Rosana D et al. (2015) Hypoxia-induced expression of phosducin-like 3 regulates expression of VEGFR-2 and promotes angiogenesis. Angiogenesis 18:449-62
Yu, Xiang; Sargaeva, Nadezda P; Thompson, Christopher J et al. (2015) In-Source Decay Characterization of Isoaspartate and ?-Peptides. Int J Mass Spectrom 390:101-109
Steinhorn, Benjamin S; Loscalzo, Joseph; Michel, Thomas (2015) Nitroglycerin and Nitric Oxide--A Rondo of Themes in Cardiovascular Therapeutics. N Engl J Med 373:277-80

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