期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 110, 期 3, 页码 948-953出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1208286110
关键词
allostery; CISD1; energy landscape theory; iron-sulfur cluster; protein frustration
资金
- Center for Theoretical Biological Physics
- National Science Foundation (NSF) [PHY-0822283, MCB-1214457]
- National Institutes of Health [GM-54038, GM101467]
- Israel Science Foundation [863/09]
- San Diego Fellowship
- Heme and Blood Proteins Training Grant [GN 5T32DK007233-34]
- Cancer Prevention and Research Institute of Texas (CPRIT)
- National Institute of General Medical Sciences Protein Structure Initiative at the Joint Center for Structural Genomics [U54GM094586]
- DOE Office of Biological and Environmental Research
- National Institutes of Health, National Institute of General Medical Sciences [P41GM103393]
- National Center for Research Resources [P41RR001209]
- Division Of Physics
- Direct For Mathematical & Physical Scien [1308264] Funding Source: National Science Foundation
- Div Of Molecular and Cellular Bioscience
- Direct For Biological Sciences [1214457] Funding Source: National Science Foundation
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 mitoNEET. We demonstrate that a loop (L2) 20 angstrom 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.
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