Strand swapping regulates the iron-sulfur cluster in the diabetes drug target mitoNEET.
MitoNEET is a recently identified diabetes drug target that coordinates a transferable 2Fe-2S cluster, and additionally contains an unusual strand swap. In this manuscript, we use a dual basin structure-based model to predict and characterize the folding and functionality of strand swapping in mitoNEET. We demonstrate that a strand unswapped conformation is kinetically accessible and that multiple levels of control are employed to regulate the conformational dynamics of the system. Environmental factors such as temperature can shift route preference toward the unswapped pathway. Additionally we see that a region recently identified as contributing to frustration in folding acts as a regulatory hinge loop that modulates conformational balance. Interestingly, strand unswapping transfers strain specifically to cluster-coordinating residues, opening the cluster-coordinating pocket. Strengthening contacts within the cluster-coordinating pocket opens a new pathway between the swapped and unswapped conformation that utilizes cracking to bypass the unfolded basin. These results suggest that local control within distinct regions affect motions important in regulating mitoNEET's 2Fe-2S clusters.
Department of Chemistry and Biochemistry, and Center for Theoretical Biological Physics, University of California at San Diego, La Jolla, CA 92093, USA.
Elizabeth Leigh
EL
Baxter
Patricia A
PA
Jennings
José N
JN
Onuchic
D000595:Amino Acid Sequence; D003198:Computer Simulation; D003920:Diabetes Mellitus / Q000188:drug therapy*; D006801:Humans; D007506:Iron-Sulfur Proteins / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D058990:Molecular Targeted Therapy; D011485:Protein Binding; D055550:Protein Stability; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013816:Thermodynamics
D007506:Iron-Sulfur Proteins; D024101:Mitochondrial Proteins