Lymphotactin: how a protein can adopt two folds

TL;DR

This paper investigates the unique dual-fold behavior of the metamorphic protein Lymphotactin using a computational model, revealing the mechanism of its conformational interconversion and suggesting such proteins may be more prevalent than previously thought.

Contribution

It demonstrates how a Ca Go-model can reproduce Lymphotactin's dual conformations and elucidates the interconversion mechanism involving a partially unfolded intermediate.

Findings

Lymphotactin adopts two distinct conformations under physiological conditions.

The interconversion occurs via a docking process through a partially unfolded state.

Shared local contacts are key to the dual-fold behavior.

Abstract

Metamorphic proteins like Lymphotactin are a notable exception of the empirical principle that structured natural proteins possess a unique three dimensional structure. In particular, the human chemokine lymphotactin protein (Ltn) exists in two distinct conformations (one monomeric and one dimeric) under physiological conditions. In this work we use a Ca Go-model to show how this very peculiar behavior can be reproduced. From the study of the thermodynamics and of the kinetics we characterize the interconversion mechanism. In particular, this takes place through the docking of the two chains living in a third monomeric, partially unfolded, state which shows a residual structure involving a set of local contacts common to the two native conformations. The main feature of two-fold proteins appears to be the sharing of a common set of local contacts between the two distinct folds as confirmed by the study of two designed two-fold proteins. Metamorphic proteins may be more common than expected.