Mardiyyah/variant-tapt_ulmfit_whole_word-LR_2e-05
Fill-Mask
•
0.1B
•
Updated
•
22
Dataset Viewer
PMCID
stringclasses 30
values | Title
stringclasses 30
values | Sentences
stringlengths 2
1.94k
|
|---|---|---|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
The immunity-related GTPases (IRGs) constitute a powerful cell-autonomous resistance system against several intracellular pathogens.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
Irga6 is a dynamin-like protein that oligomerizes at the parasitophorous vacuolar membrane (PVM) of Toxoplasma gondii leading to its vesiculation.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
Based on a previous biochemical analysis, it has been proposed that the GTPase domains of Irga6 dimerize in an antiparallel fashion during oligomerization.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
We determined the crystal structure of an oligomerization-impaired Irga6 mutant bound to a non-hydrolyzable GTP analog.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
Contrary to the previous model, the structure shows that the GTPase domains dimerize in a parallel fashion.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
The nucleotides in the center of the interface participate in dimerization by forming symmetric contacts with each other and with the switch I region of the opposing Irga6 molecule.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
The latter contact appears to activate GTP hydrolysis by stabilizing the position of the catalytic glutamate 106 in switch I close to the active site.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
Further dimerization contacts involve switch II, the G4 helix and the trans stabilizing loop.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
The Irga6 structure features a parallel GTPase domain dimer, which appears to be a unifying feature of all dynamin and septin superfamily members.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
This study contributes important insights into the assembly and catalytic mechanisms of IRG proteins as prerequisite to understand their anti-microbial action.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
Immunity-related GTPases (IRGs) comprise a family of dynamin-related cell-autonomous resistance proteins targeting intracellular pathogens, such as Mycobacterium tuberculosis , Mycobacterium avium , Listeria monocytogenes , Trypanosoma cruzi , and Toxoplasma gondii [3, 5–11].
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
In mice, the 23 IRG members are induced by interferons, whereas the single human homologue is constitutively expressed in some tissues, especially in testis .
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
In non-infected cells, most IRGs are largely cytosolic.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
However, members of a small sub-family with regulatory function associate with specific intracellular membranes, with one member favoring the endoplasmic reticulum [13, 14] and others the Golgi membrane [7, 14] and the endolysosomal system .
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
Infection by certain intracellular pathogens initiates the redistribution of several effector members to the parasitophorous vacuole, followed by its disruption [7, 14, 16, 17].
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
In this way, IRGs contribute to the release of the pathogen into the cytoplasm and its subsequent destruction.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
Irga6, one of the effector IRG proteins, localizes to the intact parasitophorous vacuole membrane (PVM) and, after disruption of the PVM, is found associated with vesicular accumulations, presumably derived from the PVM [7, 15, 18, 19].
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
A myristoylation site at Gly2 is necessary for the recruitment to the PVM but not for the weak constitutive binding to the ER membrane [14, 20].
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
An internally oriented antibody epitope on helix A between positions 20 and 24 was demonstrated to be accessible in the GTP-, but not in the GDP-bound state [20, 21].
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
This indicates large-scale structural changes upon GTP binding that probably include exposure of the myristoyl group, enhancing binding to the PVM.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
Biochemical studies indicated that Irga6 hydrolyses GTP in a cooperative manner and forms GTP-dependent oligomers in vitro and in vivo [20, 22].
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
Crystal structures of Irga6 in various nucleotide-loaded states revealed the basic architecture of IRG proteins, including a GTPase domain and a composite helical domain .
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
These studies additionally showed a dimerization interface in the nucleotide-free protein as well as in all nucleotide-bound states.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
It involves a GTPase domain surface, which is located at the opposite side of the nucleotide, and an interface in the helical domain, with a water-filled gap between the two contact surfaces.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
Mutagenesis of the contact surfaces suggests that this "backside" interface is not required for GTP-dependent oligomerization or cooperative hydrolysis, despite an earlier suggestion to the contrary .
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
Extensive biochemical studies suggested that GTP-induced oligomerization of Irga6 requires an interface in the GTPase domain across the nucleotide-binding site .
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
Recent structural studies indicated that a 'G interface' is typical of dynamin superfamily members, such as dynamin [25, 26], MxA [27, 28], the guanylate binding protein-1 (GBP-1) , atlastin [30, 31] and the bacterial dynamin-like proteins (BDLP) [32, 33].
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
For several of these proteins, formation of the G interface was shown to trigger GTP hydrolysis by inducing rearrangements of catalytic residues in cis.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
In dynamin, the G interface includes residues in the phosphate binding loop, the two switch regions, the 'trans stabilizing loop' and the 'G4 loop'.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
For Irga6, it was demonstrated that besides residues in the switch I and switch II regions, the 3'-OH group of the ribose participates in this interface .
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
Since the signal recognition particle GTPase and its homologous receptor (called FfH and FtsY in bacteria) also employ the 3'-OH ribose group to dimerize in an anti-parallel orientation therefore activating its GTPase , an analogous dimerization model was proposed for Irga6 .
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
However, the crystal structure of Irga6 in the presence of the non-hydrolyzable GTP analogue 5'-guanylyl imidodiphosphate (GMPPNP) showed only subtle differences relative to the apo or GDP-bound protein and did not reveal a new dimer interface associated with the GTPase domain .
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
This structure was obtained by soaking GMPPNP in nucleotide-free crystals of Irga6, an approach which may have interfered with nucleotide-induced domain rearrangements.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
To clarify the dimerization mode via the G interface, we determined the GMPPNP-bound crystal structure of a non-oligomerizing Irga6 variant.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
The structure revealed that Irga6 can dimerize via the G interface in a parallel head-to-head fashion.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
This dimerization mode explains previously published biochemical data, and shows in particular how the 3'-OH group of the ribose participates in the assembly.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
Our data suggest that a parallel dimerization mode may be a unifying feature in all dynamin and septin superfamily proteins.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
Previous results indicated that Irga6 mutations in a loosely defined surface region (the "secondary patch"), which is distant from the G-interface and only slightly overlapping with the backside interface (see below), individually reduced GTP-dependent oligomerization .
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
A combination of four of these mutations (R31E, K32E, K176E, and K246E) essentially eliminated GTP-dependent assembly (Additional file 1: Figure S1) and allowed crystallization of Irga6 in the presence of GMPPNP.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
Crystals diffracted to 3.2 Å resolution and displayed one exceptionally long unit cell axis of 1289 Å (Additional file 1: Table S1).
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
The structure was solved by molecular replacement and refined to Rwork/Rfree of 29.7 %/31.7 % (Additional file 1: Table S2).
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
The asymmetric unit contained seven Irga6 molecules that were arranged in a helical pattern along the long cell axis (Additional file 1: Figure S2).
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
Like other dynamin superfamily members, the GTPase domain of Irga6 comprises a canonical GTPase domain fold, with a central β-sheet surrounded by helices on both sides (Fig. 1a-c).
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
The helical domain is a bipartite structure composed of helices αA-C at the N-terminus and helix αF-L at the C-terminus of the GTPase domain.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
Overall, the seven molecules in the asymmetric unit are very similar to each other, with root mean square deviations (rmsd) ranging from 0.32 – 0.45 Å over all Cα atoms.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
The structures of the seven molecules also agree well with the previously determined structure of native GMPPNP-bound Irga6 (PDB: 1TQ6; rmsd of 1.00-1.13 Å over all Cα atoms).Fig.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
1Structure of the Irga6 dimer.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
a Schematic view of the domain architecture of mouse Irga6.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
The first and last amino acids of each domain are indicated.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
b Ribbon-type representation of the Irga6 dimer.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
In the left molecule, domains are colored according to the domain architecture, the right molecule is colored in grey.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
The nucleotide and Mg ion (green) are shown in sphere representation.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
The GTPase domain dimer is boxed.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
The dotted line indicates a 2-fold axis.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
Secondary structure was numbered according to ref. .
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
c Top view on the GTPase domain dimer.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
d Magnification of the contact sites.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
Dotted lines indicate interactions.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
e Superposition of different switch I conformations in the asymmetric unit; the same colors as in Additional file 1: Figure S2 are used for the switch I regions of the individual subunits.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
Switch I residues of subunit A (yellow) involved in ribose binding are labelled and shown in stick representation.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
Irga6 immunity-related GTPase 6 Structure of the Irga6 dimer.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
a Schematic view of the domain architecture of mouse Irga6.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
The first and last amino acids of each domain are indicated.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
b Ribbon-type representation of the Irga6 dimer.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
In the left molecule, domains are colored according to the domain architecture, the right molecule is colored in grey.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
The nucleotide and Mg ion (green) are shown in sphere representation.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
The GTPase domain dimer is boxed.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
The dotted line indicates a 2-fold axis.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
Secondary structure was numbered according to ref. .
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
c Top view on the GTPase domain dimer.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
d Magnification of the contact sites.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
Dotted lines indicate interactions.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
e Superposition of different switch I conformations in the asymmetric unit; the same colors as in Additional file 1: Figure S2 are used for the switch I regions of the individual subunits.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
Switch I residues of subunit A (yellow) involved in ribose binding are labelled and shown in stick representation.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
Irga6 immunity-related GTPase 6 The seven Irga6 molecules in the asymmetric unit form various higher order contacts in the crystals.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
Within the asymmetric unit, six molecules dimerize via the symmetric backside dimer interface (buried surface area 930 Å), and the remaining seventh molecule forms the same type of interaction with its symmetry mate of the adjacent asymmetric unit (Additional file 1: Figure S2a, b, Figure S3).
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
This indicates that the introduced mutations in the secondary patch, from which only Lys176 is part of the backside interface, do, in fact, not prevent this interaction.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
Another assembly interface with a buried surface area of 450 Å, which we call the “tertiary patch”, was formed via two interaction sites in the helical domains (Additional file 1: Figure S2c, d, S3).
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
In this interface, helices αK from two adjacent molecules form a hydrogen bonding network involving residues 373-376.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
Furthermore, two adjacent helices αA form hydrophobic contacts.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
It was previously shown that the double mutation L372R/A373R did not prevent GTP-induced assembly , so there is currently no evidence supporting an involvement of this interface in higher-order oligomerization.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
Strikingly, molecule A of one asymmetric unit assembled with an equivalent molecule of the adjacent asymmetric unit via the G-interface in a symmetric parallel fashion via a 470 Å interface.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
This assembly results in a butterfly-shaped Irga6 dimer in which the helical domains protrude in parallel orientations (Fig. 1b, Additional file 1: Figure S3).
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
In contrast, the other six molecules in the asymmetric unit do not assemble via the G interface.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
The G interface in molecule A can be subdivided into three distinct contact sites (Fig. 1c, d).
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
Contact site I is formed between R159 and K161 in the trans stabilizing loops, and S132 in the switch II regions of the opposing molecules.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
Contact site II features polar and hydrophobic interactions formed by switch I (V104, V107) with a helix following the guanine specificity motif (G4 helix, K184 and S187) and the trans stabilizing loop (T158) of the opposing GTPase domain.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
In contact site III, G103 of switch I interacts via its main chain nitrogen with the exocyclic 2’-OH and 3’-OH groups of the opposing ribose in trans, whereas the two opposing exocyclic 3’-OH group of the ribose form hydrogen bonds with each other.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
Via the ribose contact, switch I is pulled towards the opposing nucleotide (Fig. 1e).
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
In turn, E106 of switch I reorients towards the nucleotide and now participates in the coordination of the Mg ion (Fig. 1e, Additional file 1: Figure S4).
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
E106 was previously shown to be essential for catalysis , and the observed interactions in contact site III explain how dimerization via the ribose is directly coupled to the activation of GTP hydrolysis.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
The G interface is in full agreement with previously published biochemical data that indicate crucial roles of E77, G103, E106, S132, R159, K161, K162, D164, N191, and K196 for oligomerization and oligomerization-induced GTP hydrolysis .
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
All of these residues directly participate in contacts (G103, S132, R159, and K161) or are in direct vicinity to the interface (E77, E106, K162, D164, and N191).
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
Residues E77, K162, and D164 appear to orient the trans stabilizing loop which is involved in interface formation in contact site II.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
In the earlier model of an anti-parallel G interface, it was not possible to position the side chain of R159 to avoid steric conflict .
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
In the present structure, the side-chain of R159 projects laterally along the G interface and, therefore, does not cause a steric conflict.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
The buried surface area per molecule (BSA) of the G interface in Irga6 is relatively small (470 Å) compared to that of other dynamin superfamily members, such as dynamin (BSA: 1400 Å), atlastin (BSA: 820 Å), GBP-1 (BSA: 2060 Å), BDLP (BSA: 2300 Å) or the septin-related GTPase of immunity associated protein 2 (GIMAP2) (BSA: 590 Å) (Fig. 2).
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
However, the relative orientations of the GTPase domains in these dimers are strikingly similar, and the same elements, such as switch I, switch II, the trans activating and G4 loops are involved in the parallel dimerization mode in all of these GTPase families.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
Fig. 2A conserved dimerization mode via the G interface in dynamin and septin GTPases.
|
PMC4774019
|
The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.
|
The overall architecture of the parallel GTPase domain dimer of Irga6 is related to that of other dynamin and septin superfamily proteins.
|
End of preview. Expand
in Data Studio
README.md exists but content is empty.
- Downloads last month
- 47
Size of downloaded dataset files:
875 kB
Size of the auto-converted Parquet files:
875 kB
Number of rows:
9,691
Models trained or fine-tuned on Mardiyyah/TAPT-PDBE-V1