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 UniProtKB Entries

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