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Structural reconstruction of protein ancestry

Abstract

Ancestral protein reconstruction allows the resurrection and characterization of ancient proteins based on computational analyses of sequences of modern-day proteins. Unfortunately, many protein families are highly divergent and not suitable for sequence-based reconstruction approaches. This limitation is exemplified by the antigen receptors of jawed vertebrates (B- and T-cell receptors), heterodimers formed by pairs of Ig domains. These receptors are believed to have evolved from an extinct homodimeric ancestor through a process of gene duplication and diversification; however molecular evidence has so far remained elusive. Here, we use a structural approach and laboratory evolution to reconstruct such molecules and characterize their interaction with antigen. High-resolution crystal structures of reconstructed homodimeric receptors in complex with hen-egg white lysozyme demonstrate how nanomolar affinity binding of asymmetrical antigen is enabled through selective recruitment and structural plasticity within the receptor-binding site. Our results provide structural evidence in support of long-held theories concerning the evolution of antigen receptors, and provide a blueprint for the experimental reconstruction of protein ancestry in the absence of phylogenetic evidence.

Type Journal
Authors Rouet, R.; Langley, DB.; Schofield,P.; Christie, M.; Roome, B.; Porebski, BT.; Buckle,AM.; Clifton, BE.; Jackson, CJ.; Stock, D.; Christ, D.
Responsible Garvan Author A/Prof Daniel Christ
Publisher Name PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Published Date 2017-04-11
Published Volume 114
Published Issue 5
Published Pages 3897-3902
Status Published in-print
DOI 10.1073/pnas.1613477114
URL link to publisher's version https://www.ncbi.nlm.nih.gov/pubmed/28356519
OpenAccess link to author's accepted manuscript version https://publications.gimr.garvan.org.au/open-access/14020