19 angstrom solution structure of the filarial nematode immunomodulatory protein, ES-62

Ackerman, C. J., Harnett, M. M. , Harnett, W., Kelly, S. M. , Svergun, D. I. and Byron, O. (2003) 19 angstrom solution structure of the filarial nematode immunomodulatory protein, ES-62. Biophysical Journal, 84(1), pp. 489-500. (doi: 10.1016/S0006-3495(03)74868-1) (PMID:12524301) (PMCID:PMC1302629)

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Abstract

ES-62, a protein secreted by filarial nematodes, parasites of vertebrates including humans, has an unusual posttranslational covalent addition of phosphorylcholine to an N-type glycan. Studies on ES-62 from the rodent parasite Acanthocheilonema viteae ascribe it a dominant role in ensuring parasite survival by modulating the host immune system. Understanding this immunomodulation at the molecular level awaits full elucidation but distinct components of ES-62 may participate: the protein contributes aminopeptidase-like activity whereas the phosphorylcholine is thought to act as a signal transducer. We have used biophysical and bioinformatics-based structure prediction methods to define a low-resolution model of ES-62. Sedimentation equilibrium showed that ES-62 is a tightly bound tetramer. The sedimentation coefficient is consistent with this oligomer and the overall molecular shape revealed by small angle x-ray scattering. A 19 Å model for ES-62 was restored from the small-angle x-ray scattering data using the program DAMMIN which uses simulated annealing to find a configuration of densely packed scattering elements consistent with the experimental scattering curve. Analysis of the primary sequence with the position-specific iterated basic local alignment search tool, PSI-BLAST, identified six closely homologous proteins, five of which are peptidases, consistent with observed aminopeptidase activity in ES-62. Differences between the secondary structure content of ES-62 predicted using the consensus output from the secondary structure prediction server JPRED and measured using circular dichroism are discussed in relation to multimeric glycosylated proteins. This study represents the first attempt to understand the multifunctional properties of this important parasite-derived molecule by studying its structure.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Harnett, Professor Margaret and Kelly, Dr Sharon and Harnett, Professor William and Byron, Professor Olwyn
Authors: Ackerman, C. J., Harnett, M. M., Harnett, W., Kelly, S. M., Svergun, D. I., and Byron, O.
College/School:College of Medical Veterinary and Life Sciences > School of Life Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Biophysical Journal
Publisher:Elsevier (Cell Press)
ISSN:0006-3495
ISSN (Online):1542-0086

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