Decoding protein metalation and mis-metalation

Metalloproteins drive the reactions of life. Discover how to predict and correct mis-metalation in engineered biology.
Decoding protein metalation and mis-metalation
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We have written this blog in the hope it might encourage someone who does not normally think about metals in biology to engage with this work: Especially if that someone is interested in Engineering Biology. The purpose is to draw attention to how half of the reactions of life come to be catalysed by the specialised chemistries of the correct metals bound to enzymes.

     2017 was the last time a member of our research group, Deenah Osman, wrote a Research Communities blog. The new paper is the culmination of Deenah’s discoveries in Nature Communications 2017 and Nature Chemical Biology, 2019, along with those of past and present group members described in Nature Communications, 2021, Nature Chemical Biology, 2017 and Nature 2008. In the new paper we finally show that it is possible to understand and predict which metals bind to enzymes and other proteins inside cells (the speciation of metalation). The work has implications across biology, chemical biology, and especially engineering biology for sustainable biomanufacturing.

     The new paper describes the use of a protein that traps metals to directly test predictions of in vivo metalation. The protein was discovered in a cyanobacterium where it traps manganese. It previously revealed that the specificity of metalation can depend on metal availabilities at protein folding Nature, 2008. But this suggests that mis-metalation could occur if a protein is mis-matched to metal availabilities, for example when expressed in a heterologous cell. Since 2008, the intervening papers have calibrated DNA-binding metal sensors so that intracellular metal availabilities can be estimated. Using these estimations a metalation calculator was produced Nature Communications, 2021, Metallomics, 2022. However, the metalation predictions had not previously been directly tested because proteins typically exchange metals post-extraction. But this constraint would not apply to a protein that traps metals. In the present work, bio-inorganic chemist Tessa Young developed an experimental approach using pairs of buffered metals at folding to first determine the cyanobacterial manganese protein’s in vitro metal preferences. Arthur Glasfeld, Chemist and Structural Biologist (a purportedly retired Professor from Oregon) came to Durham to work closely with Biologist Sophie Clough and the team to complete these assays.

    The metalation calculations, and hence the underlying mechanisms, are validated in the new paper. The research predicted, and then confirmed, that the manganese protein is mis-metalated with iron when expressed in E. coli. This means that metalation will not be a fait accompli in Engineering Biology. This is one reason why we are eager for these discoveries to reach a broad audience, and especially those interested in Engineering Biology. It’s estimated that about a half of enzymes, and a third of all proteins, bind metals (Nature, 2009). This suggests widespread opportunities to use such calculations to optimise biomanufacturing by optimising metalation inside engineered organisms.   

     The paper also describes how metalation can be predictably switched in cells supplemented with metals. Blueprints and calculators have been produced to help others to predict in-cell metalation, without (necessarily) having to read our research group’s outputs over many years. The calculations make it possible to predictably engineer metalation of up to half the reactions of life, and to engineer in cell metalation of artificial metalloenzmes. The new paper also shows how the cyanobacterial manganese protein can be used to refine estimated metal availabilities which in turn uncovered how cobalt alters the availability of intracellular iron.

     We are indebted to the Biotechnology and Biosciences Research Council (BBSRC) and its predecessor Research Councils for providing continuity of support, by funding our research on metals in biology for more than four decades. We are excited that a BBSRC research hub ELEMENTAL is now starting to nurture interactions between the Engineering Biology and Metals in Biology communities.

    The new paper was only possible due to creative interactions within a multidisciplinary team of co-authors, with expertise across biology and bio-inorganic chemistry, plus the accumulated discoveries of a roll call of present and past group members trained in a variety of disciplines and sub-disciplines. Finally, the foundational work of our former colleague Deenah Osman, to whom the paper is dedicated, merits special mention. 

    This work was supported by Biotechnology and Biological Sciences Research Council awards BB/W015749/1 (NJR), Understanding mis-metalation of native versus heterologously expressed protein, and BB/V006002/1 (NJR), A calculator for metalation inside a cell, along with BB/S009787/1 (NJR) supporting networking in Industrial Biotechnology. The ELEMENTAL HUB is funded by  BB/Y008456/1 (MJW/PTC/NJR).

 Sophie Clough and Nigel Robinson, Biosciences and Chemistry Departments, Durham University, UK.

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Physical Sciences > Chemistry > Biological Chemistry > Bioinorganic Chemistry
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