How an epidermal growth factor (EGF)-like domain binds calcium

High resolution NMR structure of the calcium form of the NH2-terminal EGF-like domain in coagulation factor X

Maria Selander, Magnus Ullner, Egon Persson, Olle Teleman, Johan Stenflo, Torbjörn Drakenberg

Research output: Contribution to journalArticleScientificpeer-review

167 Citations (Scopus)

Abstract

Domains homologous to the epidermal growth factor (EGF) are important building blocks for extracellular proteins. Proteins containing these domains have been shown to function in such diverse biological processes as blood coagulation, complement activation, and the developmental determination of embryonic cell fates. Many of these proteins require calcium for their biological function. In the case of coagulation factors IX and X and anticoagulants proteins C and S, calcium has been found to bind to the EGF-like domains. We have now determined the three-dimensional structure of the calcium-bound form of the NH2-terminal EGF-like domain in coagulation factor X by two-dimensional NMR and simulated folding. Ligands to the calcium ion are the two backbone carbonyls in Gly-47 and Gly-64, as well as the side chains in Gln-49, erythro-beta-hydroxyaspartic acid (Hya) 63, and possibly Asp-46. The conserved Asp-48 is not a ligand in our present structures. The remaining ligands are assumed to be solvent molecules or, in the intact protein, ligands from neighboring domains. Other proteins interacting in a calcium-dependent manner may also contribute ligands. A comparison with the calcium-free form shows that calcium binding induces strictly local structural changes in the domain. Residues corresponding to the side chain ligands in factor X are conserved in many other proteins, such as the integral membrane protein TAN-1 of human lymphocytes and its developmentally important homolog, Notch, in Drosophila. Calcium binding to EGF-like domains may be crucial for numerous protein-protein interactions involving EGF-like domains in coagulation factors, plasma proteins, and membrane proteins. Therefore, there is reason to believe that this novel calcium site plays an important role in the biochemistry of extracellular proteins.
Original languageEnglish
Pages (from-to)19642-19649
Number of pages8
JournalJournal of Biological Chemistry
Volume267
Issue number27
Publication statusPublished - 1992
MoE publication typeA1 Journal article-refereed

Fingerprint

Factor X
Epidermal Growth Factor
Nuclear magnetic resonance
Calcium
Ligands
Proteins
Membrane Proteins
Triacetoneamine-N-Oxyl
Biological Phenomena
Biochemistry
Factor IX
Blood Coagulation Factors
Lymphocytes
Complement Activation
Protein S
Blood Coagulation
Protein C
Coagulation
Anticoagulants
Drosophila

Cite this

Selander, Maria ; Ullner, Magnus ; Persson, Egon ; Teleman, Olle ; Stenflo, Johan ; Drakenberg, Torbjörn. / How an epidermal growth factor (EGF)-like domain binds calcium : High resolution NMR structure of the calcium form of the NH2-terminal EGF-like domain in coagulation factor X. In: Journal of Biological Chemistry. 1992 ; Vol. 267, No. 27. pp. 19642-19649.
@article{51e841e6129d4f70b9f17bb9c3d7e89d,
title = "How an epidermal growth factor (EGF)-like domain binds calcium: High resolution NMR structure of the calcium form of the NH2-terminal EGF-like domain in coagulation factor X",
abstract = "Domains homologous to the epidermal growth factor (EGF) are important building blocks for extracellular proteins. Proteins containing these domains have been shown to function in such diverse biological processes as blood coagulation, complement activation, and the developmental determination of embryonic cell fates. Many of these proteins require calcium for their biological function. In the case of coagulation factors IX and X and anticoagulants proteins C and S, calcium has been found to bind to the EGF-like domains. We have now determined the three-dimensional structure of the calcium-bound form of the NH2-terminal EGF-like domain in coagulation factor X by two-dimensional NMR and simulated folding. Ligands to the calcium ion are the two backbone carbonyls in Gly-47 and Gly-64, as well as the side chains in Gln-49, erythro-beta-hydroxyaspartic acid (Hya) 63, and possibly Asp-46. The conserved Asp-48 is not a ligand in our present structures. The remaining ligands are assumed to be solvent molecules or, in the intact protein, ligands from neighboring domains. Other proteins interacting in a calcium-dependent manner may also contribute ligands. A comparison with the calcium-free form shows that calcium binding induces strictly local structural changes in the domain. Residues corresponding to the side chain ligands in factor X are conserved in many other proteins, such as the integral membrane protein TAN-1 of human lymphocytes and its developmentally important homolog, Notch, in Drosophila. Calcium binding to EGF-like domains may be crucial for numerous protein-protein interactions involving EGF-like domains in coagulation factors, plasma proteins, and membrane proteins. Therefore, there is reason to believe that this novel calcium site plays an important role in the biochemistry of extracellular proteins.",
author = "Maria Selander and Magnus Ullner and Egon Persson and Olle Teleman and Johan Stenflo and Torbj{\"o}rn Drakenberg",
year = "1992",
language = "English",
volume = "267",
pages = "19642--19649",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "27",

}

How an epidermal growth factor (EGF)-like domain binds calcium : High resolution NMR structure of the calcium form of the NH2-terminal EGF-like domain in coagulation factor X. / Selander, Maria; Ullner, Magnus; Persson, Egon; Teleman, Olle; Stenflo, Johan; Drakenberg, Torbjörn.

In: Journal of Biological Chemistry, Vol. 267, No. 27, 1992, p. 19642-19649.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - How an epidermal growth factor (EGF)-like domain binds calcium

T2 - High resolution NMR structure of the calcium form of the NH2-terminal EGF-like domain in coagulation factor X

AU - Selander, Maria

AU - Ullner, Magnus

AU - Persson, Egon

AU - Teleman, Olle

AU - Stenflo, Johan

AU - Drakenberg, Torbjörn

PY - 1992

Y1 - 1992

N2 - Domains homologous to the epidermal growth factor (EGF) are important building blocks for extracellular proteins. Proteins containing these domains have been shown to function in such diverse biological processes as blood coagulation, complement activation, and the developmental determination of embryonic cell fates. Many of these proteins require calcium for their biological function. In the case of coagulation factors IX and X and anticoagulants proteins C and S, calcium has been found to bind to the EGF-like domains. We have now determined the three-dimensional structure of the calcium-bound form of the NH2-terminal EGF-like domain in coagulation factor X by two-dimensional NMR and simulated folding. Ligands to the calcium ion are the two backbone carbonyls in Gly-47 and Gly-64, as well as the side chains in Gln-49, erythro-beta-hydroxyaspartic acid (Hya) 63, and possibly Asp-46. The conserved Asp-48 is not a ligand in our present structures. The remaining ligands are assumed to be solvent molecules or, in the intact protein, ligands from neighboring domains. Other proteins interacting in a calcium-dependent manner may also contribute ligands. A comparison with the calcium-free form shows that calcium binding induces strictly local structural changes in the domain. Residues corresponding to the side chain ligands in factor X are conserved in many other proteins, such as the integral membrane protein TAN-1 of human lymphocytes and its developmentally important homolog, Notch, in Drosophila. Calcium binding to EGF-like domains may be crucial for numerous protein-protein interactions involving EGF-like domains in coagulation factors, plasma proteins, and membrane proteins. Therefore, there is reason to believe that this novel calcium site plays an important role in the biochemistry of extracellular proteins.

AB - Domains homologous to the epidermal growth factor (EGF) are important building blocks for extracellular proteins. Proteins containing these domains have been shown to function in such diverse biological processes as blood coagulation, complement activation, and the developmental determination of embryonic cell fates. Many of these proteins require calcium for their biological function. In the case of coagulation factors IX and X and anticoagulants proteins C and S, calcium has been found to bind to the EGF-like domains. We have now determined the three-dimensional structure of the calcium-bound form of the NH2-terminal EGF-like domain in coagulation factor X by two-dimensional NMR and simulated folding. Ligands to the calcium ion are the two backbone carbonyls in Gly-47 and Gly-64, as well as the side chains in Gln-49, erythro-beta-hydroxyaspartic acid (Hya) 63, and possibly Asp-46. The conserved Asp-48 is not a ligand in our present structures. The remaining ligands are assumed to be solvent molecules or, in the intact protein, ligands from neighboring domains. Other proteins interacting in a calcium-dependent manner may also contribute ligands. A comparison with the calcium-free form shows that calcium binding induces strictly local structural changes in the domain. Residues corresponding to the side chain ligands in factor X are conserved in many other proteins, such as the integral membrane protein TAN-1 of human lymphocytes and its developmentally important homolog, Notch, in Drosophila. Calcium binding to EGF-like domains may be crucial for numerous protein-protein interactions involving EGF-like domains in coagulation factors, plasma proteins, and membrane proteins. Therefore, there is reason to believe that this novel calcium site plays an important role in the biochemistry of extracellular proteins.

M3 - Article

VL - 267

SP - 19642

EP - 19649

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 27

ER -