The three-dimensional structure of an H-superfamily conotoxin reveals a granulin fold arising from a common ICK cysteine framework
| Autor: | Anastasia Albert, Lars Ellgaard, Mads M. Foged, Terje Vasskog, Samuel D. Robinson, Cecilie L. Søltoft, Raymond S. Norton, Baldomero M. Olivera, Kaare Teilum, Andreas B. Bertelsen, Anthony W. Purcell, Lau Dalby Nielsen, Steen V. Petersen, Helena Safavi-Hemami |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Protein Folding Magnetic Resonance Spectroscopy Cysteine/chemistry granulin Granulin PROTEIN Peptide Biochemistry Protein structure STACK Conotoxin Disulfides Protein disulfide-isomerase toxin CYSTINE KNOT Granulins chemistry.chemical_classification Granulins/chemistry biology Protein Stability CD spectroscopy inhibitor cystine knot Recombinant Proteins FAMILY protein-disulfide isomerase THERAPEUTICS Protein Structure and Folding conotoxin VENOM PEPTIDES Stereochemistry PHASE Mollusk Venoms Conus Snail/metabolism 03 medical and health sciences NMR spectroscopy protein conformation antistasin Animals Conus victoriae Amino Acid Sequence Cysteine protein structure Recombinant Proteins/biosynthesis protein evolution Molecular Biology protein expression 030102 biochemistry & molecular biology Conus Snail Cell Biology biology.organism_classification 2 BETA-HAIRPINS 030104 developmental biology chemistry Conotoxins/chemistry Mollusk Venoms/metabolism disulfide bond Protein Conformation beta-Strand Inhibitor cystine knot CHEMICAL-SHIFTS Conotoxins Disulfides/chemistry hairpin COEFFICIENTS disulfide |
| Zdroj: | Nielsen, L D, Foged, M M, Albert, A, Bertelsen, A B, Søltoft, C L, Robinson, S D, Petersen, S V, Purcell, A W, Olivera, B M, Norton, R S, Vasskog, T, Safavi-Hemami, H, Teilum, K & Ellgaard, L 2019, ' The three-dimensional structure of an H-superfamily conotoxin reveals a granulin fold arising from a common ICK cysteine framework ', The Journal of Biological Chemistry, vol. 294, no. 22, pp. 8745-8759 . https://doi.org/10.1074/jbc.RA119.007491 Nielsen, L D, Foged, M M, Albert, A, Bertelsen, A B, Søltoft, C L, Robinson, S D, Petersen, S V, Purcell, A W, Olivera, B M, Norton, R S, Vasskog, T, Safavi-Hemami, H, Teilum, K & Ellgaard, L 2019, ' The three-dimensional structure of an H-superfamily conotoxin reveals a granulin fold arising from a common ICK cysteine framework ', The Journal of biological chemistry . https://doi.org/10.1074/jbc.RA119.007491 J Biol Chem Nielsen, L D, Foged, M M, Albert, A, Bertelsen, A B, Søltoft, C L, Robinson, S D, Petersen, S V, Purcell, A W, Olivera, B M, Norton, R S, Vasskog, T, Safavi-Hemami, H, Teilum, K & Ellgaard, L 2019, ' The three-dimensional structure of an H-superfamily conotoxin reveals a granulin fold arising from a common ICK cysteine framework ', Journal of Biological Chemistry, vol. 294, no. 22, pp. 8745-8759 . https://doi.org/10.1074/jbc.RA119.007491 |
| DOI: | 10.1074/jbc.RA119.007491 |
| Popis: | Venomous marine cone snails produce peptide toxins (conotoxins) that bind ion channels and receptors with high specificity and therefore are important pharmacological tools. Conotoxins contain conserved cysteine residues that form disulfide bonds that stabilize their structures. To gain structural insight into the large, yet poorly characterized conotoxin H-superfamily, we used NMR and CD spectroscopy along with MS-based analyses to investigate H-Vc7.2 from Conus victoriae, a peptide with a VI/VII cysteine framework. This framework has CysI-CysIV/CysII-CysV/CysIII-CysVI connectivities, which have invariably been associated with the inhibitor cystine knot (ICK) fold. However, the solution structure of recombinantly expressed and purified H-Vc7.2 revealed that although it displays the expected cysteine connectivities, H-Vc7.2 adopts a different fold consisting of two stacked -hairpins with opposing -strands connected by two parallel disulfide bonds, a structure homologous to the N-terminal region of the human granulin protein. Using structural comparisons, we subsequently identified several toxins and nontoxin proteins with this “mini-granulin” fold. These findings raise fundamental questions concerning sequence-structure relationships within peptides and proteins and the key determinants that specify a given fold. |
| Databáze: | OpenAIRE |
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