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Structure. 2014 Jan 7;22(1):9-21. doi: 10.1016/j.str.2013.10.005. Epub 2013 Nov 21.

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

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  • 1Genomics Research Center, Academia Sinica, Taipei 115, Taiwan; Chemical Biology and Molecular Biophysics Program, Taiwan International Graduate Program, Institute of Biological Chemistry, Academia¬†Sinica, Taipei 115, Taiwan; Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei 106, Taiwan.
  • 2Genomics Research Center, Academia Sinica, Taipei 115, Taiwan; Institute of Biomedical Informatics, National Yang-Ming University, Taipei 11221, Taiwan; Bioinformatics Program, Taiwan International Graduate Program, Institute of Information Science, Academia Sinica, Taipei 115, Taiwan.
  • 3Genomics Research Center, Academia Sinica, Taipei 115, Taiwan.
  • 4Genomics Research Center, Academia Sinica, Taipei 115, Taiwan; Institute of Zoology, College of Life Sciences, National Taiwan University, Taipei 106, Taiwan.
  • 5Genomics Research Center, Academia Sinica, Taipei 115, Taiwan; Genome and Systems Biology Degree Program, National Taiwan University, Taipei 106, Taiwan.
  • 6Genomics Research Center, Academia Sinica, Taipei 115, Taiwan. Electronic address: yangas@gate.sinica.edu.tw.

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.

Copyright © 2014 Elsevier Ltd. All rights reserved.

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