Conformational catalysis of cataract-associated aggregation by interacting intermediates in a human eye lens crystallin

TL;DR

This paper uncovers how intermolecular domain interface interactions in human eye lens crystallin promote misfolding and aggregation, contributing to cataract formation, with implications for multi-domain protein behavior.

Contribution

It reveals a novel mechanism of conformational catalysis via interface stealing in two-domain proteins, advancing understanding of protein misfolding in cataracts.

Findings

Intermolecular domain interfaces outcompete native intramolecular interfaces.

Loss of native interface promotes misfolding and aggregation.

Interface stealing may be common in multi-domain proteins.

Abstract

Most known proteins in nature consist of multiple domains. Interactions between domains may lead to unexpected folding and misfolding phenomena. This study of human {\gamma}D-crystallin, a two-domain protein in the eye lens, revealed one such surprise: conformational catalysis of misfolding via intermolecular domain interface ''stealing''. An intermolecular interface between the more stable domains outcompetes the native intramolecular domain interface. Loss of the native interface in turn promotes misfolding and subsequent aggregation, especially in cataract-related {\gamma}D-crystallin variants. This phenomenon is likely a contributing factor in the development of cataract disease, the leading worldwide cause of blindness. However, interface stealing likely occurs in many proteins composed of two or more interacting domains.