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Crystal structure of human importin-?1 (Rch1), revealing a potential autoinhibition mode involving homodimerization.

ABSTRACT: In this study, we determined the crystal structure of N-terminal importin-?-binding domain (IBB)-truncated human importin-?1 (?IBB-h-importin-?1) at 2.63 Å resolution. The crystal structure of ?IBB-h-importin-?1 reveals a novel closed homodimer. The homodimer exists in an autoinhibited state in which both the major and minor nuclear localization signal (NLS) binding sites are completely buried in the homodimerization interface, an arrangement that restricts NLS binding. Analytical ultracentrifugation studies revealed that ?IBB-h-importin-?1 is in equilibrium between monomers and dimers and that NLS peptides shifted the equilibrium toward the monomer side. This finding suggests that the NLS binding sites are also involved in the dimer interface in solution. These results show that when the IBB domain dissociates from the internal NLS binding sites, e.g., by binding to importin-?, homodimerization possibly occurs as an autoinhibition state.

SUBMITTER: Miyatake H

PROVIDER: S-EPMC4319847 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Crystal structure of human importin-α1 (Rch1), revealing a potential autoinhibition mode involving homodimerization.

Miyatake Hideyuki H Sanjoh Akira A Unzai Satoru S Matsuda Go G Tatsumi Yuko Y Miyamoto Yoichi Y Dohmae Naoshi N Aida Yoko Y

PloS one 20150206 2

In this study, we determined the crystal structure of N-terminal importin-β-binding domain (IBB)-truncated human importin-α1 (ΔIBB-h-importin-α1) at 2.63 Å resolution. The crystal structure of ΔIBB-h-importin-α1 reveals a novel closed homodimer. The homodimer exists in an autoinhibited state in which both the major and minor nuclear localization signal (NLS) binding sites are completely buried in the homodimerization interface, an arrangement that restricts NLS binding. Analytical ultracentrifug ...[more]

PMID: 25658636

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Project description:Adenylylsulfate reductase (adenosine 5'-phosphosulfate [APS] reductase [APSR]) plays a key role in catalyzing APS to sulfite in dissimilatory sulfate reduction. Here, we report the crystal structure of APSR from Desulfovibrio gigas at 3.1-A resolution. Different from the alpha(2)beta(2)-heterotetramer of the Archaeoglobus fulgidus, the overall structure of APSR from D. gigas comprises six alphabeta-heterodimers that form a hexameric structure. The flavin adenine dinucleotide is noncovalently attached to the alpha-subunit, and two [4Fe-4S] clusters are enveloped by cluster-binding motifs. The substrate-binding channel in D. gigas is wider than that in A. fulgidus because of shifts in the loop (amino acid 326 to 332) and the alpha-helix (amino acid 289 to 299) in the alpha-subunit. The positively charged residue Arg160 in the structure of D. gigas likely replaces the role of Arg83 in that of A. fulgidus for the recognition of substrates. The C-terminal segment of the beta-subunit wraps around the alpha-subunit to form a functional unit, with the C-terminal loop inserted into the active-site channel of the alpha-subunit from another alphabeta-heterodimer. Electrostatic interactions between the substrate-binding residue Arg282 in the alpha-subunit and Asp159 in the C terminus of the beta-subunit affect the binding of the substrate. Alignment of APSR sequences from D. gigas and A. fulgidus shows the largest differences toward the C termini of the beta-subunits, and structural comparison reveals notable differences at the C termini, activity sites, and other regions. The disulfide comprising Cys156 to Cys162 stabilizes the C-terminal loop of the beta-subunit and is crucial for oligomerization. Dynamic light scattering and ultracentrifugation measurements reveal multiple forms of APSR upon the addition of AMP, indicating that AMP binding dissociates the inactive hexamer into functional dimers, presumably by switching the C terminus of the beta-subunit away from the active site. The crystal structure of APSR, together with its oligomerization properties, suggests that APSR from sulfate-reducing bacteria might self-regulate its activity through the C terminus of the beta-subunit.

Dataset Information

Crystal structure of human importin-?1 (Rch1), revealing a potential autoinhibition mode involving homodimerization.

Publications

Crystal structure of human importin-α1 (Rch1), revealing a potential autoinhibition mode involving homodimerization.

Similar Datasets

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