| 1. |
- Szatmari, Peter, et al.
(author)
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Mapping autism risk loci using genetic linkage and chromosomal rearrangements.
- 2007
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 39:3, s. 319-328
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Journal article (peer-reviewed)abstract
- Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,168 families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs.
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| 2. |
- Abramson, Jeff
(author)
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Structural studies on the integral membrane protein, ubiquinol oxidase from Escherichia coli
- 2001
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Doctoral thesis (other academic/artistic)abstract
- Heme-copper oxidases are redox-driven proton pumps that couple the reduction of molecular oxygen to water with the vectorial translocation of protons across the membrane. The proton gradient generated by heme-copper oxidases and the other members of the aerobic respiratory chain is ultimately used to drive the synthesis of ATP. There are two main branches of the heme-copper oxidases that are characterized by the electron donating substrate; the cytochrome c oxidases, which use cytochrome c as the electron donor, and the ubiquinol oxidases, which use a lipid-soluble molecule, ubiquinol, as their electron donor. These enzymes share important structural and functional features. This thesis presents the procedures that have led to the first crystal structure of a ubiquinol oxidase, cytochrome bo, oxidase from Escherichia coli, at a resolution of 3.5 Å. The overall structure of the enzyme is similar to those of cytochrome c oxidases; however the membrane spanning region of subunit I contains a cluster of polar residues exposed to the interior of the lipid bilayer. No such structural feature is present in cytochrome c oxidases. Mutagenesis studies on residues in this region strongly suggest that this area forms a ubiquinone binding site. A comparison of this region with known ubiquinone binding sites shows remarkable similarities. In light of these findings specific roles for these polar residues is proposed in electron and proton transfer in ubiquinol oxidase. A fusion protein of cytochrome bo3-Protein Z was generated in an attempt to increase the hydrophilic surface of the protein, thus extending protein-protein contacts within the crystal lattice structure. Such an approach can be used to facilitate crystallization.
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| 3. |
- Pantazis, Antonios, et al.
(author)
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Harnessing photoinduced electron transfer to optically determine protein sub-nanoscale atomic distances
- 2018
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In: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 9
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Journal article (peer-reviewed)abstract
- Proteins possess a complex and dynamic structure, which is influenced by external signals and may change as they perform their biological functions. We present an optical approach, distance-encoding photoinduced electron transfer (DEPET), capable of the simultaneous study of protein structure and function. An alternative to FRET-based methods, DEPET is based on the quenching of small conjugated fluorophores by photoinduced electron transfer: a reaction that requires contact of the excited fluorophore with a suitable electron donor. This property allows DEPET to exhibit exceptional spatial and temporal resolution capabilities in the range pertinent to protein conformational change. We report the first implementation of DEPET on human large-conductance K+ (BK) channels under voltage clamp. We describe conformational rearrangements underpinning BK channel sensitivity to electrical excitation, in conducting channels expressed in living cells. Finally, we validate DEPET in synthetic peptide length standards, to evaluate its accuracy in measuring sub-and near-nanometer intramolecular distances.
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| 4. |
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| 5. |
- Teijido, Oscar, et al.
(author)
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Affixing N-terminal α-Helix to the Wall of the Voltage-dependent Anion Channel Does Not Prevent Its Voltage Gating
- 2012
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In: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 287:14, s. 11437-11445
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Journal article (peer-reviewed)abstract
- The voltage-dependent anion channel (VDAC) governs the free exchange of ions and metabolites between the mitochondria and the rest of the cell. The three-dimensional structure of VDAC1 reveals a channel formed by 19 beta-strands and an N-terminal alpha-helix located near the midpoint of the pore. The position of this alpha-helix causes a narrowing of the cavity, but ample space for metabolite passage remains. The participation of the N-terminus of VDAC1 in the voltage-gating process has been well established, but the molecular mechanism continues to be debated; however, the majority of models entail large conformational changes of this N-terminal segment. Here we report that the pore-lining N-terminal alpha-helix does not undergo independent structural rearrangements during channel gating. We engineered a double Cys mutant in murine VDAC1 that cross-links the alpha-helix to the wall of the beta-barrel pore and reconstituted the modified protein into planar lipid bilayers. The modified murine VDAC1 exhibited typical voltage gating. These results suggest that the N-terminal alpha-helix is located inside the pore of VDAC in the open state and remains associated with beta-strand 11 of the pore wall during voltage gating.
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| 6. |
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| 7. |
- Wahlgren, Weixiao Yuan, 1970, et al.
(author)
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Substrate-bound outward-open structure of a Na+-coupled sialic acid symporter reveals a new Na+ site.
- 2018
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1
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Journal article (peer-reviewed)abstract
- Many pathogenic bacteria utilise sialic acids as an energy source or use them as an external coating to evade immune detection. As such, bacteria that colonise sialylated environments deploy specific transporters to mediate import of scavenged sialic acids. Here, we report a substrate-bound 1.95Å resolution structure and subsequent characterisation of SiaT, a sialic acid transporter from Proteus mirabilis. SiaT is a secondary active transporter of the sodium solute symporter (SSS) family, which use Na+ gradients to drive the uptake of extracellular substrates. SiaT adopts the LeuT-fold and is in an outward-open conformation in complex with the sialic acid N-acetylneuraminic acid and two Na+ ions. One Na+ binds to the conserved Na2 site, while the second Na+ binds to a new position, termed Na3, which is conserved in many SSS family members. Functional and molecular dynamics studies validate the substrate-binding site and demonstrate that both Na+ sites regulate N-acetylneuraminic acid transport.
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| 8. |
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