The three-dimensional structure of an H-superfamily conotoxin reveals a granulin fold arising from a common ICK cysteine framework

Lau D Nielsen; Mads M. Foged; Anastasia Albert; Andreas B. Bertelsen; Cecilie L Søltoft; Samuel D. Robinson; Steen Vang Petersen; Anthony W. Purcell; Baldomero M. Olivera; Raymond S. Norton; Terje Vasskog; Helena Safavi-Hemami; Kaare Teilum; Lars Ellgaard

doi:10.1074/jbc.ra119.007491

The three-dimensional structure of an H-superfamily conotoxin reveals a granulin fold arising from a common ICK cysteine framework

Lau D Nielsen, Mads M. Foged, Anastasia Albert, Andreas B. Bertelsen, Cecilie L Søltoft, Samuel D. Robinson, Steen Vang Petersen, Anthony W. Purcell, Baldomero M. Olivera, Raymond S. Norton, Terje Vasskog, Helena Safavi-Hemami, Kaare Teilum, Lars Ellgaard

8 Citationer (Scopus)

Abstract

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 Cys^I-Cys^IV/Cys^II-Cys^V/Cys^III-Cys^VI 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.

Originalsprog	Engelsk
Tidsskrift	The Journal of Biological Chemistry
Vol/bind	294
Udgave nummer	22
Sider (fra-til)	8745-8759
ISSN	0021-9258
DOI	https://doi.org/10.1074/jbc.ra119.007491
Status	Udgivet - 31 maj 2019

FN’s Verdensmål

Dette resultat bidrager til følgende verdensmål

Adgang til dokumentet

10.1074/jbc.ra119.007491

http://www.jbc.org/content/294/22/8745.full.pdfLicens: CC BY

Citationsformater

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, 294(22), 8745-8759. https://doi.org/10.1074/jbc.ra119.007491

Nielsen, LD, Foged, MM, Albert, A, Bertelsen, AB, Søltoft, CL, Robinson, SD, Petersen, SV, Purcell, AW, Olivera, BM, Norton, RS, 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, bind 294, nr. 22, s. 8745-8759. https://doi.org/10.1074/jbc.ra119.007491

@article{9a6f9a14de9a4f62adfb2ff58a676733,

title = "The three-dimensional structure of an H-superfamily conotoxin reveals a granulin fold arising from a common ICK cysteine framework",

abstract = "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.",

author = "Nielsen, {Lau D} and Foged, {Mads M.} and Anastasia Albert and Bertelsen, {Andreas B.} and S{\o}ltoft, {Cecilie L} and Robinson, {Samuel D.} and Petersen, {Steen Vang} and Purcell, {Anthony W.} and Olivera, {Baldomero M.} and Norton, {Raymond S.} and Terje Vasskog and Helena Safavi-Hemami and Kaare Teilum and Lars Ellgaard",

note = "Published under license by The American Society for Biochemistry and Molecular Biology, Inc.",

year = "2019",

month = may,

day = "31",

doi = "10.1074/jbc.ra119.007491",

language = "English",

volume = "294",

pages = "8745--8759",

journal = "Journal of Biological Chemistry",

issn = "0021-9258",

publisher = "American Society for Biochemistry and Molecular Biology, Inc.",

number = "22",

}

TY - JOUR

T1 - The three-dimensional structure of an H-superfamily conotoxin reveals a granulin fold arising from a common ICK cysteine framework

AU - Nielsen, Lau D

AU - Foged, Mads M.

AU - Albert, Anastasia

AU - Bertelsen, Andreas B.

AU - Søltoft, Cecilie L

AU - Robinson, Samuel D.

AU - Petersen, Steen Vang

AU - Purcell, Anthony W.

AU - Olivera, Baldomero M.

AU - Norton, Raymond S.

AU - Vasskog, Terje

AU - Safavi-Hemami, Helena

AU - Teilum, Kaare

AU - Ellgaard, Lars

N1 - Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

PY - 2019/5/31

Y1 - 2019/5/31

N2 - 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.

AB - 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.

U2 - 10.1074/jbc.ra119.007491

DO - 10.1074/jbc.ra119.007491

M3 - Journal article

C2 - 30975904

SN - 0021-9258

VL - 294

SP - 8745

EP - 8759

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 22

ER -

The three-dimensional structure of an H-superfamily conotoxin reveals a granulin fold arising from a common ICK cysteine framework

Abstract

FN’s Verdensmål

Adgang til dokumentet

Fingeraftryk

Citationsformater