Allosteric control in a metalloprotein dramatically alters function

Elizabeth Leigh Baxter, John A. Zuris, Charles Wang, Phu Luong T. Vo, Herbert L. Axelrod, Aina E. Cohen, Mark L. Paddock, Rachel Nechushtai, Jose N. Onuchic, Patricia A. Jennings*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Scopus citations


Metalloproteins (MPs) comprise one-third of all known protein structures. This diverse set of proteins contain a plethora of unique inorganic moieties capable of performing chemistry that would otherwise be impossible using only the amino acids found in nature. Most of the well-studied MPs are generally viewed as being very rigid in structure, and it is widely thought that the properties of the metal centers are primarily determined by the small fraction of amino acids that make up the local environment. Here we examine both theoretically and experimentally whether distal regions can influence the metal center in the diabetes drug target mitoEET. We demonstrate that a loop (L2) 20 Å away from the metal center exerts allosteric control over the cluster binding domain and regulates multiple properties of the metal center. Mutagenesis of L2 results in significant shifts in the redox potential of the [2Fe-2S] cluster and orders of magnitude effects on the rate of [2Fe-2S] cluster transfer to an apo-acceptor protein. These surprising effects occur in the absence of any structural changes. An examination of the native basin dynamics of the protein using all-atom simulations shows that twisting in L2 controls scissoring in the cluster binding domain and results in perturbations to one of the cluster-coordinating histidines. These allosteric effects are in agreement with previous folding simulations that predicted L2 could communicate with residues surrounding the metal center. Our findings suggest that long-range dynamical changes in the protein backbone can have a significant effect on the functional properties of MPs.

Original languageAmerican English
Pages (from-to)948-953
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number3
StatePublished - 15 Jan 2013


  • Allostery
  • CISD1
  • Energy landscape theory
  • Iron-sulfur cluster
  • Protein frustration


Dive into the research topics of 'Allosteric control in a metalloprotein dramatically alters function'. Together they form a unique fingerprint.

Cite this