The disordered N-terminus modulates the conformational metamorphosis of IscU, the Fe-S cluster assembly protein

Abstract

An iron-sulfur (Fe-S) cluster is a ubiquitous and essential cofactor for various proteins, and its imbalance can cause abnormal iron accumulation and lead to fatal diseases, such as ataxia and myopathy. The biosynthesis of Fe-S clusters depends on several critical proteins, among which IscU, the Fe-S cluster assembly protein, plays a pivotal role. IscU shows a ‘metamorphic’ structural feature; it exhibits two interconverting conformations, the structured state (S-state) and the disordered state (D-state), and both conformations have their own functionality and interaction network. However, the detailed mechanism regarding how IscU maintains its structural heterogeneity has remained enigmatic. In this study, we employed interdisciplinary approaches to elucidate that the order-disorder transition in the N-terminal region of IscU is important to modulate its metamorphic feature. We found that the degree of orderliness in the N-terminal region is positively related to the S-state stabilization, while IscU’s affinity for HscA is inversely correlated. This implies that the N-terminal disorder of IscU is maintained on purpose to optimize its physiological efficacy. We propose that this study provides unprecedented insights into the development of novel therapeutic molecules for related pathogenic processes.