Loop-sequence features and stability determinants in antibody variable domains by high-throughput experiments

Hung Ju Chang, Jhih Wei Jian, Hung Ju Hsu, Yu Ching Lee, Hong Sen Chen, Jhong Jhe You, Shin Chen Hou, Chih Yun Shao, Yen Ju Chen, Kuo Ping Chiu, Hung Pin Peng, Kuo Hao Lee, An Suei Yang

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18 Citations (Scopus)

Abstract

Protein loops are frequently considered as critical determinants in protein structure and function. Recent advances in high-throughput methods for DNA sequencing and thermal stability measurement have enabled effective exploration of sequence-structure-function relationships in local protein regions. Using these data-intensive technologies, we investigated the sequence-structure- function relationships of six complementarity-determining regions (CDRs) and ten non-CDR loops in the variable domains of a model vascular endothelial growth factor (VEGF)-binding single-chain antibody variable fragment (scFv) whose sequence had been optimized via a consensus-sequence approach. The results show that only a handful of residues involving long-range tertiary interactions distant from the antigen-binding site are strongly coupled with antigen binding. This implies that the loops are passive regions in protein folding; the essential sequences of these regions are dictated by conserved tertiary interactions and the consensus local loop-sequence features contribute little to protein stability and function.

Original languageEnglish
Pages (from-to)9-21
Number of pages13
JournalStructure
Volume22
Issue number1
DOIs
Publication statusPublished - Jan 7 2014
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Structural Biology

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    Chang, H. J., Jian, J. W., Hsu, H. J., Lee, Y. C., Chen, H. S., You, J. J., Hou, S. C., Shao, C. Y., Chen, Y. J., Chiu, K. P., Peng, H. P., Lee, K. H., & Yang, A. S. (2014). Loop-sequence features and stability determinants in antibody variable domains by high-throughput experiments. Structure, 22(1), 9-21. https://doi.org/10.1016/j.str.2013.10.005