UEA researchers uncover how ancient protein-bound iron cofactors are assembled in bacteria

Published by  Communications

On 1st Nov 2022

Chemical molecules

Mass spectrometric studies of the assembly of an essential and common iron- and sulfur-containing cofactor has revealed a ‘sulfur first’ mechanism.

Practically all of life is dependent on small molecules made of iron and sulfur (called iron-sulfur clusters), which are attached to proteins, and are amongst the most ancient of all protein cofactors. They play key roles in essential processes such as the conversion of energy stored in food (or light) into a useable form in respiration (or photosynthesis). These iron-sulfur clusters do not form spontaneously, and need to be assembled in the cell. This process poses an important problem: iron and sulfur are elements that are essential for life but, at the same time, are also intrinsically toxic. Nature has thus engineered complex and tightly regulated molecular machines to synthesise iron-sulfur clusters and attach them to proteins in an orderly and regulated way. These machines are evolutionarily conserved across the kingdoms of life and all discovered within the past 25 years.

The importance of these machines for human life is illustrated by the number of diseases, such as Friedreich’s ataxia, which increasingly appear to be connected with impairment of iron-sulfur cluster proteins and their assembly. When any of the parts of these machines break down, disease occurs.

While an increasingly sophisticated understanding of the iron-sulfur cluster assembly machines of humans and bacteria is slowly emerging, we are still far from having a complete picture. Understanding the steps involved in formation of the cluster is limited by the lack of detailed information on the precise sequence of events and nature of intermediates, which interactions are formed and how they regulate the overall process. The UEA team have previously developed a vital research tool to understand such processes in iron-sulfur cluster proteins, based on native mass spectrometry, and this has allowed them to unpick the mechanism in the bacterial Isc iron-sulfur cluster assembly system.

The team, led by Dr Jason Crack and Prof Nick Le Brun from the School of Chemistry at UEA, and involving researchers from King’s College London, showed that the assembly process is largely concerted, meaning that intermediates do not accumulate, and that either iron or sulfur can initiate the process by binding to the scaffold protein IscU. However, IscU is commonly found with zinc bound at the assembly site. The team found that, when IscU is in this form, only the transfer of sulfur to IscU can initiate the assembly process. A sulfur-controlled mechanism is consistent with the known regulation of the formation of sulfur from cysteine by the Isc system.

The work was published this week in Chemical Science, DOI: 10.1039/D2SC04169C and is part of the 2022 Chemical Science HOT Article Collection.

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