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Design of a binding scaffold based on variable lymphocyte receptors of jawless vertebrates by module engineering.


ABSTRACT: Repeat proteins have recently been of great interest as potential alternatives to immunoglobulin antibodies due to their unique structural and biophysical features. We here present the development of a binding scaffold based on variable lymphocyte receptors, which are nonimmunoglobulin antibodies composed of Leucine-rich repeat modules in jawless vertebrates, by module engineering. A template scaffold was first constructed by joining consensus repeat modules between the N- and C-capping motifs of variable lymphocyte receptors. The N-terminal domain of the template scaffold was redesigned based on the internalin-B cap by analyzing the modular similarity between the respective repeat units using a computational approach. The newly designed scaffold, termed "Repebody," showed a high level of soluble expression in bacteria, displaying high thermodynamic and pH stabilities. Ease of molecular engineering was shown by designing repebodies specific for myeloid differentiation protein-2 and hen egg lysozyme, respectively, by a rational approach. The crystal structures of designed repebodies were determined to elucidate the structural features and interaction interfaces. We demonstrate general applicability of the scaffold by selecting repebodies with different binding affinities for interleukin-6 using phage display.

SUBMITTER: Lee SC 

PROVIDER: S-EPMC3295290 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Design of a binding scaffold based on variable lymphocyte receptors of jawless vertebrates by module engineering.

Lee Sang-Chul SC   Park Keunwan K   Han Jieun J   Lee Joong-jae JJ   Kim Hyun Jung HJ   Hong Seungpyo S   Heu Woosung W   Kim Yu Jung YJ   Ha Jae-Seok JS   Lee Seung-Goo SG   Cheong Hae-Kap HK   Jeon Young Ho YH   Kim Dongsup D   Kim Hak-Sung HS  

Proceedings of the National Academy of Sciences of the United States of America 20120210 9


Repeat proteins have recently been of great interest as potential alternatives to immunoglobulin antibodies due to their unique structural and biophysical features. We here present the development of a binding scaffold based on variable lymphocyte receptors, which are nonimmunoglobulin antibodies composed of Leucine-rich repeat modules in jawless vertebrates, by module engineering. A template scaffold was first constructed by joining consensus repeat modules between the N- and C-capping motifs o  ...[more]

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