Use of molecular modeling and site-directed mutagenesis to define the structural basis for the immune response to carbohydrate xenoantigens.

Use of molecular modeling and site-directed mutagenesis to define the structural basis for the immune response to carbohydrate xenoantigens. Research Abstract Details 

Research Abstract Table of Contents

Jump to the:

Use of molecular modeling and site-directed mutagenesis to define the structural basis for the immune response to carbohydrate xenoantigens. Abstract Text:

Mary Kearns-Jonker,Natasha Barteneva,Robert Mencel,Namath Hussain,Irina Shulkin,Alan Xu,Margaret Yew,Donald V Cramer,

BACKGROUND: Natural antibodies directed at carbohydrates reject porcine xenografts. They are initially expressed in germline configuration and are encoded by a small number of structurally-related germline progenitors. The transplantation of genetically-modified pig organs prevents hyperacute rejection, but delayed graft rejection still occurs, partly due to humoral responses. IgVH genes encoding induced xenoantibodies are predominantly, not exclusively, derived from germline progenitors in the VH3 family. We have previously identified the immunoglobulin heavy chain genes encoding VH3 xenoantibodies in patients and primates. In this manuscript, we complete the structural analysis of induced xenoantibodies by identifying the IgVH genes encoding the small proportion of VH4 xenoantibodies and the germline progenitors encoding xenoantibody light chains. This information has been used to define the xenoantibody/carbohydrate binding site using computer-simulated modeling. RESULTS: The VH4-59 gene encodes antibodies in the VH4 family that are induced in human patients mounting active xenoantibody responses. The light chain of xenoantibodies is encoded by DPK5 and HSIGKV134. The structural information obtained by sequencing analysis was used to create computer-simulated models. Key contact sites for xenoantibody/carbohydrate interaction for VH3 family xenoantibodies include amino acids in sites 31, 33, 50, 57, 58 and the CDR3 region of the IgVH gene. Site-directed mutagenesis indicates that mutations in predicted contact sites alter binding to carbohydrate xenoantigens. Computer-simulated modeling suggests that the CDR3 region directly influences binding. CONCLUSION: Xenoantibodies induced during early and delayed xenograft responses are predominantly encoded by genes in the VH3 family, with a small proportion encoded by VH4 germline progenitors. This restricted group can be identified by the unique canonical structure of the light chain, heavy chain and CDR3. Computer-simulated models depict this structure with accuracy, as confirmed by site-directed mutagenesis. Computer-simulated drug design using computer-simulated models may now be applied to develop new drugs that may enhance the survival of xenografted organs.

Use of molecular modeling and site-directed mutagenesis to define the structural basis for the immune response to carbohydrate xenoantigens. Publishing Authors By Initials

M Kearns-Jonker,N Barteneva,R Mencel,N Hussain,I Shulkin,A Xu,M Yew,DV Cramer,

For similar animals: chordata: vertebrates: mammals: artiodactyla: swine research abstracts see: animals: chordata: vertebrates: mammals: artiodactyla: swine research

PUBMED ID PMID:

MEDLINE DATE:

Use of molecular modeling and site-directed mutagenesis to define the structural basis for the immune response to carbohydrate xenoantigens. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: BMC immunology

VOLUME: 8

Page Numbers: 3

Journal Abbreviation:

ISSN: 1471-2172

DAY: 12

MONTH: 03

YEAR: 2007

Use of molecular modeling and site-directed mutagenesis to define the structural basis for the immune response to carbohydrate xenoantigens. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 100966980

Use of molecular modeling and site-directed mutagenesis to define the structural basis for the immune response to carbohydrate xenoantigens. Keywords Mesh Terms:

KEYWORDS: Swine

MESH TERMS: immunology

Chemical & Substance for Abstract: Use of molecular modeling and site-directed mutagenesis to define the structural basis for the immune response to carbohydrate xenoantigens. Information

Substance Name: Epitopes

Registry Number: 0

Grant and Affiliation Information for Use of molecular modeling and site-directed mutagenesis to define the structural basis for the immune response to carbohydrate xenoantigens.

AFFILIATION: Department of Cardiothoracic Surgery, Saban Research Institute of the Children's Hospital of Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA 90027 USA. mkearns@chla.usc.edu

Country: England

AGENCY: United States NIAID

GRANT: R01AI52079

ACRONYM: AI

MEDLINETA: BMC Immunol

REFSOURCE:

DATABASENAME:

ACCESSION NUMBER:

Number Hits: 0

Use of molecular modeling and site-directed mutagenesis to define the structural basis for the immune response to carbohydrate xenoantigens Related Publications

• A New Wavelet-based Technique For Analyzing Surface Mechanomyographic Signals: 1664: Board #154 May 30 2:00 PM - 3:30 PM.
• A novel mutation in the GRHPR gene in a Japanese patient with primary hyperoxaluria type 2.
• Auditory brainstem neural activation patterns are altered in EphA4- and ephrin-B2-deficient mice.
• Can an ancillary ligand lead to a thermodynamically stable end-on 1 : 1 Cu-O2 adduct supported by a beta-diketiminate ligand?
• Characterization of the structure and reactivity of monocopper-oxygen complexes supported by beta-diketiminate and anilido-imine ligands.
• Chromatographic alignment of LC-MS and LC-MS/MS datasets by genetic algorithm feature extraction.
• Complications of high tibial osteotomy with external fixation in adolescent Blount's disease.
• Deletion of EphA4 enhances deafferentation-induced ipsilateral sprouting in auditory brainstem projections.
• Dynamics of an [Fe4S4(SPh)4]2- cluster explored via IR, Raman, and nuclear resonance vibrational spectroscopy (NRVS)-analysis using 36S substitution, DFT calculations, and empirical force fields.
• EphA4 misexpression alters tonotopic projections in the auditory brainstem.
• Ginkgo biloba and ovarian cancer prevention: epidemiological and biological evidence.
• High-Resolution X-ray Fluorescence and Excitation Spectroscopy of Metalloproteins.
• How nitrogenase shakes--initial information about P-cluster and FeMo-cofactor normal modes from nuclear resonance vibrational spectroscopy (NRVS).
• Investigation of multi-modal high-salt binding ion-exchange chromatography using quantitative structure-property relationship modeling.
• Methods for integrating medication compliance and persistence in pharmacoeconomic evaluations.
• Minimum length requirement of the flexible N-terminal translocation subdomain of colicin E3.
• Observation of terahertz vibrations in Pyrococcus furiosus rubredoxin via impulsive coherent vibrational spectroscopy and nuclear resonance vibrational spectroscopy--interpretation by molecular mechanics.
• Pathology of thrombotic thrombocytopenic purpura in the placenta, with emphasis on the snowman sign.
• Pooling of case specimens to create standard serum sets for screening cancer biomarkers.
• Preliminary morphological evidence that vertebral hypomobility induces synaptic plasticity in the spinal cord.
• Protein adsorption isotherm behavior in hydrophobic interaction chromatography.
• Proteomic analysis reveals differences between Vitis vinifera L. cv. Chardonnay and cv. Cabernet Sauvignon and their responses to water deficit and salinity.
• Quantitative proteomics using uniform (15)N-labeling, MASCOT, and the trans-proteomic pipeline.
• Serum Peptide Profiling using MALDI Mass Spectrometry: avoiding the Pitfalls of Coated Magnetic Beads using Well-established ZipTip Technology.
• Structure of the complex of the colicin E2 R-domain and its BtuB receptor. The outer membrane colicin translocon.
• Systematic assessment of training-induced changes in corticospinal output to hand using frameless stereotaxic transcranial magnetic stimulation.
• The xenoantibody response and immunoglobulin gene expression profile of cynomolgus monkeys transplanted with hDAF-transgenic porcine hearts.
• Transcript abundance profiles reveal larger and more complex responses of grapevine to chilling compared to osmotic and salinity stress.
• Use of molecular modeling and site-directed mutagenesis to define the structural basis for the immune response to carbohydrate xenoantigens.
• Validation of density functional modeling protocols on experimental bis(mu-oxo)/mu-eta2:eta2-peroxo dicopper equilibria.