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Crystal structure of the ATPase domain of the human AAA+ protein paraplegin/SPG7.

Karlberg T, van den Berg S, Hammarström M, Sagemark J, Johansson I, Holmberg-Schiavone L, Schüler H - PLoS ONE (2009)

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View Article: PubMed Central - PubMed

Affiliation: Structural Genomics Consortium, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.

ABSTRACT

Unlabelled: Paraplegin is an m-AAA protease of the mitochondrial inner membrane that is linked to hereditary spastic paraplegias. The gene encodes an FtsH-homology protease domain in tandem with an AAA+ homology ATPase domain. The protein is believed to form a hexamer that uses ATPase-driven conformational changes in its AAA-domain to deliver substrate peptides to its protease domain. We present the crystal structure of the AAA-domain of human paraplegin bound to ADP at 2.2 A. This enables assignment of the roles of specific side chains within the catalytic cycle, and provides the structural basis for understanding the mechanism of disease mutations.

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Model of the paraplegin hexamer.A. The hexameric structure of paraplegin305–565 was modelled by aligning our crystal structure (blue) with each monomer within the T. thermophilus FtsH hexamer crystal structure (2dhr; orange). The outline of one monomer is indicated by grey shading, and the N- and C-termini of another monomer are indicated. The boxed area is expanded in panel B. B. Close-up of the region around the pore loops and the monomer interface around the nucleotide binding site. The hydrophobic pore loop residue Phe228 of FtsH, implicated in substrate binding, is shown in green, and the corresponding paraplegin residue Ile832 is shown in purple. Paraplegin Arg470, shown in red, is a putative arginine finger that activates ATP hydrolysis in the neighbor monomer following a conformational change in the ring structure.
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pone-0006975-g005: Model of the paraplegin hexamer.A. The hexameric structure of paraplegin305–565 was modelled by aligning our crystal structure (blue) with each monomer within the T. thermophilus FtsH hexamer crystal structure (2dhr; orange). The outline of one monomer is indicated by grey shading, and the N- and C-termini of another monomer are indicated. The boxed area is expanded in panel B. B. Close-up of the region around the pore loops and the monomer interface around the nucleotide binding site. The hydrophobic pore loop residue Phe228 of FtsH, implicated in substrate binding, is shown in green, and the corresponding paraplegin residue Ile832 is shown in purple. Paraplegin Arg470, shown in red, is a putative arginine finger that activates ATP hydrolysis in the neighbor monomer following a conformational change in the ring structure.

Mentions: Given the high degree of similarity between paraplegin and FtsH, superposition of our paraplegin AAA-domain structure with the hexameric ring structures of FtsH (2dhr; 1iy1) can reveal common mechanism as well as distinct properties of paraplegin. This analysis shows that in the paraplegin hexamer, the N-terminus and the C-terminal α-helical bundle are expected at high radius, while the segment between β2 and α3 are predicted to lie near the central pore (Figure 5). The α-helical bundle has a threefold role during the chemo-mechanical cycle: 1. A conserved arginine at the N-terminal end of the bundle has been suggested to act as an arginine finger, extending into the active site of the neighboring subunit within the ring and stabilizing the charge developing during the transition state of ATP hydrolysis [19], [22]. In paraplegin, Arg 470 is positioned to act as an arginine finger. 2. As detailed above, sensor 2 motif (at the N-terminus of α7) is likely involved in coupling conformational changes resulting from ATP hydrolysis to the neighbor monomer within the AAA-ring. 3. The bundle is positioned to couple conformational changes resulting from ATP hydrolysis to the underlying protease ring.


Crystal structure of the ATPase domain of the human AAA+ protein paraplegin/SPG7.

Karlberg T, van den Berg S, Hammarström M, Sagemark J, Johansson I, Holmberg-Schiavone L, Schüler H - PLoS ONE (2009)

Model of the paraplegin hexamer.A. The hexameric structure of paraplegin305–565 was modelled by aligning our crystal structure (blue) with each monomer within the T. thermophilus FtsH hexamer crystal structure (2dhr; orange). The outline of one monomer is indicated by grey shading, and the N- and C-termini of another monomer are indicated. The boxed area is expanded in panel B. B. Close-up of the region around the pore loops and the monomer interface around the nucleotide binding site. The hydrophobic pore loop residue Phe228 of FtsH, implicated in substrate binding, is shown in green, and the corresponding paraplegin residue Ile832 is shown in purple. Paraplegin Arg470, shown in red, is a putative arginine finger that activates ATP hydrolysis in the neighbor monomer following a conformational change in the ring structure.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2734466&req=5

pone-0006975-g005: Model of the paraplegin hexamer.A. The hexameric structure of paraplegin305–565 was modelled by aligning our crystal structure (blue) with each monomer within the T. thermophilus FtsH hexamer crystal structure (2dhr; orange). The outline of one monomer is indicated by grey shading, and the N- and C-termini of another monomer are indicated. The boxed area is expanded in panel B. B. Close-up of the region around the pore loops and the monomer interface around the nucleotide binding site. The hydrophobic pore loop residue Phe228 of FtsH, implicated in substrate binding, is shown in green, and the corresponding paraplegin residue Ile832 is shown in purple. Paraplegin Arg470, shown in red, is a putative arginine finger that activates ATP hydrolysis in the neighbor monomer following a conformational change in the ring structure.
Mentions: Given the high degree of similarity between paraplegin and FtsH, superposition of our paraplegin AAA-domain structure with the hexameric ring structures of FtsH (2dhr; 1iy1) can reveal common mechanism as well as distinct properties of paraplegin. This analysis shows that in the paraplegin hexamer, the N-terminus and the C-terminal α-helical bundle are expected at high radius, while the segment between β2 and α3 are predicted to lie near the central pore (Figure 5). The α-helical bundle has a threefold role during the chemo-mechanical cycle: 1. A conserved arginine at the N-terminal end of the bundle has been suggested to act as an arginine finger, extending into the active site of the neighboring subunit within the ring and stabilizing the charge developing during the transition state of ATP hydrolysis [19], [22]. In paraplegin, Arg 470 is positioned to act as an arginine finger. 2. As detailed above, sensor 2 motif (at the N-terminus of α7) is likely involved in coupling conformational changes resulting from ATP hydrolysis to the neighbor monomer within the AAA-ring. 3. The bundle is positioned to couple conformational changes resulting from ATP hydrolysis to the underlying protease ring.

Bottom Line: This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions.Please note that a web plugin is required to access this enhanced functionality.Instructions for the installation and use of the web plugin are available in Text S1.

View Article: PubMed Central - PubMed

Affiliation: Structural Genomics Consortium, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.

ABSTRACT

Unlabelled: Paraplegin is an m-AAA protease of the mitochondrial inner membrane that is linked to hereditary spastic paraplegias. The gene encodes an FtsH-homology protease domain in tandem with an AAA+ homology ATPase domain. The protein is believed to form a hexamer that uses ATPase-driven conformational changes in its AAA-domain to deliver substrate peptides to its protease domain. We present the crystal structure of the AAA-domain of human paraplegin bound to ADP at 2.2 A. This enables assignment of the roles of specific side chains within the catalytic cycle, and provides the structural basis for understanding the mechanism of disease mutations.

Enhanced version: This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available in Text S1.

Show MeSH
Related in: MedlinePlus