Antibody evolution constrains conformational heterogeneity by tailoring protein dynamics


Abstract

The evolution of proteins with novel function is thought to start from precursor proteins that are conformationally heterogeneous. The corresponding genes may be duplicated and then mutated to select and optimize a specific conformation. However, testing this idea has been difficult because of the challenge of quantifying protein flexibility and conformational heterogeneity as a function of evolution. Here, we report the characterization of protein heterogeneity and dynamics as a function of evolution for the antifluorescein antibody 4-4-20. Using nonlinear laser spectroscopy, surface plasmon resonance, and molecular dynamics simulations, we demonstrate that evolution localized the Ab-combining site from a heterogeneous ensemble of conformations to a single conformation by introducing mutations that act cooperatively and over significant distances to rigidify the protein. This study demonstrates how protein dynamics may be tailored by evolution and has important implications for our understanding of how novel protein functions are evolved.

Submission Details

ID: pPcLSu4G

Submitter: Stephanie Contreras

Submission Date: June 26, 2020, 10:36 a.m.

Version: 1

Publication Details
Jörg Zimmermann, Erin L. Oakman, Ian F. Thorpe, Xinghua Shi, Paul Abbyad, Charles L. Brooks III, Steven G. Boxer, Floyd E. Romesberg,Proceedings of the National Academy of Sciences of United States of America (2006) Antibody evolution constrains conformational heterogeneity by tailoring protein dynamics
Additional Information

Structure view and single mutant data analysis

Study data

No weblogo for data of varying length.
Colors: D E R H K S T N Q A V I L M F Y W C G P
 

Data Distribution

Studies with similar sequences (approximate matches)

Correlation with other assays (exact sequence matches)


Relevant PDB Entries

Structure ID Release Date Resolution Structure Title
1CFN 1999-03-19T00:00:00+0000 2.65 ANTI-P24 (HIV-1) FAB FRAGMENT CB41 COMPLEXED WITH AN EPITOPE-RELATED PEPTIDE
1HH6 2000-12-21T00:00:00+0000 2.6 ANTI-P24 (HIV-1) FAB FRAGMENT CB41 COMPLEXED WITH A PEPTIDE
1FRG 1994-01-17T00:00:00+0000 2.8 CRYSTAL STRUCTURE, SEQUENCE, AND EPITOPE MAPPING OF A PEPTIDE COMPLEX OF AN ANTI-INFLUENZA HA PEPTIDE ANTIBODY FAB 26(SLASH)9: FINE-TUNING ANTIBODY SPECIFICITY
1CFQ 1999-03-19T00:00:00+0000 2.8 ANTI-P24 (HIV-1) FAB FRAGMENT CB41
1CFT 1999-03-19T00:00:00+0000 2.8 ANTI-P24 (HIV-1) FAB FRAGMENT CB41 COMPLEXED WITH AN EPITOPE-UNRELATED D-PEPTIDE
1CFS 1999-03-19T00:00:00+0000 2.75 ANTI-P24 (HIV-1) FAB FRAGMENT CB41 COMPLEXED WITH AN EPITOPE-UNRELATED PEPTIDE
1HH9 2000-12-21T00:00:00+0000 2.7 ANTI-P24 (HIV-1) FAB FRAGMENT CB41 COMPLEXED WITH A PEPTIDE
1HI6 2001-01-02T00:00:00+0000 2.55 ANTI-P24 (HIV-1) FAB FRAGMENT CB41 COMPLEXED WITH A PEPTIDE
1BOG 1998-08-04T00:00:00+0000 2.6 ANTI-P24 (HIV-1) FAB FRAGMENT CB41 COMPLEXED WITH AN EPITOPE-HOMOLOGOUS PEPTIDE
1SVZ 2004-03-30T00:00:00+0000 1.89 Crystal structure of the single-chain Fv fragment 1696 in complex with the epitope peptide corresponding to N-terminus of HIV-2 protease

Relevant UniProtKB Entries

Percent Identity Matching Chains Protein Accession Entry Name
95.5 VL(gl) P01631 KV2A7_MOUSE
100.0 L Ig gamma-2A chain C region, membrane-bound form,4-4-20 (IG*G2A=KAPPA=) FAB FRAGMENT P01837 IGKC_MOUSE
94.0 H Ig gamma-2A chain C region, membrane-bound form,4-4-20 (IG*G2A=KAPPA=) FAB FRAGMENT P01864 GCAB_MOUSE
100.0 H Ig gamma-2A chain C region, membrane-bound form,4-4-20 (IG*G2A=KAPPA=) FAB FRAGMENT P01865 GCAM_MOUSE
100.0 H Ig gamma-2A chain C region, membrane-bound form,4-4-20 (IG*G2A=KAPPA=) FAB FRAGMENT P01863 GCAA_MOUSE