Database accession: MF7000747
Name: Human MitoNEET, double mutant G66A, D67A
PDB ID: 4f2c
Experimental method: X-ray (1.35 Å)
Assembly: Homodimer
Source organism: Homo sapiens
Primary publication of the structure:
Baxter EL, Zuris JA, Wang C, Vo PL, Axelrod HL, Cohen AE, Paddock ML, Nechushtai R, Onuchic JN, Jennings PA
Allosteric control in a metalloprotein dramatically alters function.
(2013) Proc. Natl. Acad. Sci. U.S.A. 110: 948-53
PMID: 23271805
Abstract:
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 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.
Annotations from the GeneOntology database. Only terms that fit at least two of the interacting proteins are shown. Molecular function:
2 iron, 2 sulfur cluster binding 2 iron, 2 sulfur cluster binding
identical protein binding identical protein binding
L-cysteine transaminase activity L-cysteine transaminase activity
metal ion binding metal ion binding
protein homodimerization activity protein homodimerization activity
pyridoxal phosphate binding pyridoxal phosphate binding
Biological process:
protein maturation by [2Fe-2S] cluster transfer protein maturation by [2Fe-2S] cluster transfer
regulation of autophagy regulation of autophagy
regulation of cellular respiration regulation of cellular respiration
Cellular component:
mitochondrial outer membrane mitochondrial outer membrane
mitochondrion mitochondrion
Structural annotations of the participating protein chains.Entry contents: 2 distinct polypeptide molecules
Chains: A, B
Notes: All chains according to the most probable oligomerization state stored in PDBe were considered.
Number of unique protein segments: 1
Name: CDGSH iron-sulfur domain-containing protein 1
Source organism: Homo sapiens
Length: 108 residues
Sequence:Sequence according to the corresponding UniProt protein segmentMSLTSSSSVRVEWIAAVTIAAGTAAIGYLAYKRFYVKDHRNKAMINLHIQKDNPKIVHAFDMEDLGDKAVYCRCWRSKKFPFCDGAHTKHNEETGDNVGPLIIKKKET
UniProtKB AC: Q9NZ45 (positions: 40-108)
Coverage: 63%
Name: CDGSH iron-sulfur domain-containing protein 1
Source organism: Homo sapiens
Length: 108 residues
Sequence:Sequence according to the corresponding UniProt protein segmentMSLTSSSSVRVEWIAAVTIAAGTAAIGYLAYKRFYVKDHRNKAMINLHIQKDNPKIVHAFDMEDLGDKAVYCRCWRSKKFPFCDGAHTKHNEETGDNVGPLIIKKKET
UniProtKB AC: Q9NZ45 (positions: 42-105)
Coverage: 59%
Evidence demonstrating that the participating proteins are unstructured prior to the interaction and their folding is coupled to binding. Representative domain in related structures: Iron-binding zinc finger CDGSH type
Evidence level: Indirect evidence
Evidence coverage: The full structure participates in mutual synergistic folding.
Complex Evidence:
Size exclusion chromatography measurements suggest that mitoNEET33–108 protein exists as a dimer in solution (PMID:17905743). The monomers associate along their full length to form an intertwined structure with an extensive interface (PMID:17766439).
Chain A:
N/A
Chain B:
N/A
Surface and contacts features:
Structures from the PDB that contain the same number of proteins, and the proteins from the two structures show a sufficient degree of pairwise similarity, i.e. they belong to the same UniRef90 cluster (the full proteins exhibit at least 90% sequence identity) and convey roughly the same region to their respective interactions (the two regions from the two proteins share a minimum of 70% overlap). Download the CIF file (.cif)
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