EGF-like domain

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EGF-like domain
PDB 1hre EBI.jpg
Structure of the epidermal growth factor-like domain of heregulin-alpha. [1]
Identifiers
SymbolEGF
Pfam PF00008
Pfam clan CL0001
InterPro IPR000742
PROSITE PDOC00021
SCOP2 1apo / SCOPe / SUPFAM
CDD cd00053
EGF-like domain, extracellular
PDB 1jv2 EBI.jpg
crystal structure of the extracellular segment of integrin alphavbeta3
Identifiers
SymbolEGF_2
Pfam PF07974
Pfam clan CL0001
InterPro IPR013111
CDD cd00054

The EGF-like domain is an evolutionary conserved protein domain, which derives its name from the epidermal growth factor where it was first described. It comprises about 30 to 40 amino-acid residues and has been found in a large number of mostly animal proteins. [2] [3] Most occurrences of the EGF-like domain are found in the extracellular domain of membrane-bound proteins or in proteins known to be secreted. An exception to this is the prostaglandin-endoperoxide synthase. The EGF-like domain includes 6 cysteine residues which in the epidermal growth factor have been shown to form 3 disulfide bonds. The structures of 4-disulfide EGF-domains have been solved from the laminin and integrin proteins. The main structure of EGF-like domains is a two-stranded β-sheet followed by a loop to a short C-terminal, two-stranded β-sheet. These two β-sheets are usually denoted as the major (N-terminal) and minor (C-terminal) sheets. [4] EGF-like domains frequently occur in numerous tandem copies in proteins: these repeats typically fold together to form a single, linear solenoid domain block as a functional unit.

Contents

Subtypes

Despite the similarities of EGF-like domains, distinct domain subtypes have been identified. [5] The two main proposed types of EGF-like domains are the human EGF-like (hEGF) domain and the complement C1r-like (cEGF) domain, [4] which was first identified in the human complement protease C1r. [5] C1r is a highly specific serine protease initiating the classical pathway of complement activation during immune response. [6] Both the hEGF- and cEGF-like domains contain three disulfides and derive from a common ancestor that carried four disulfides of which one was lost during evolution. Furthermore, cEGF-like domains can be divided in two subtypes (1 and 2) whereas all hEGF-like domains belong to one subtype. [4]

The differentiation of cEGF-like and hEGF-like domains and their subtypes is based on structural features and the connectivity of their disulfide bonds. cEGF- and hEGF-like domains have a distinct shape and orientation of the minor sheet and one C-terminal half-cystine has a different position. The lost cysteines of the common ancestor differ between cEGF- and hEGF-like domains and hence these types differ in their disulfide linkages. The differentiation of cEGF into subtype 1 and 2, which probably occurred after its split from hEGF, is based on different residue numbers between the distinct half-cystines. An N-terminal located calcium binding motif can be found in hEGF- as well as in cEGF-like domains and is therefore not suitable to tell them apart. [4]

hEGF- and cEGF-like domains also contain post-translational modifications, which are often unusual and differ between hEGF- and cEGF-like domains. These post-translational modifications include O-glycosylations, mostly O-fucose modifications, and β-hydroxylation of aspartate and asparagine residues. O-fucose modifications have only been detected in hEGF-like domains and they are important for the proper folding of the hEGF-like domain. β-Hydroxylation appears in hEGF- and cEGF-like domains, the former is hydroxylated on an aspartic acid while the latter is hydroxylated on an asparagine residue. The biological role of this post-translational modification is unclear, [4] but mice with a knockout of the aspartyl-β-hydroxylation enzyme show developmental defects. [7]

Proteins containing EGF-like domains are widespread and can be exclusively hEGF- or cEGF-like, or contain a mix of both. In many mitogenic and developmental proteins such as Notch and Delta the EGF-like domains are only of the hEGF type. Other proteins contain only cEGF such as thrombomodulin and the LDL-receptor. In mixed EGF-proteins the hEGF- and cEGF-like domains are grouped together with the hEGFs always being N-terminal of the cEGFs. Such proteins are involved in blood coagulation or are components of the extracellular matrix like fibrillin and LTBP-1 (Latent-transforming growth factor beta-binding protein 1). In addition to the aforementioned three disulfide hEGF- and cEGF-like types, there are proteins carrying a four-disulfide EGF-like domain like laminin and integrin. [4]

The two main EGF-like domain subtypes hEGF and cEGF are not just distinct in their structure and conformation but also have different functions. This hypothesis is substantiated by research on LTBP-1. LTBP-1 anchors the transforming growth factor β (TGF-β) to the extracellular matrix. hEGF-like domains play a role in targeting the LTBP-1/TGF-β assembly to the extracellular matrix. Once attached to the extracellular matrix, TGF-β dissociates from hEGF subunits to allow its subsequent activation. cEGF-like domains seem to play an unspecific role in this activation by promoting the cleavage of LTBP-1 from TGF-β by various proteases. [4]

In conclusion, although distinct EGF-like domains are grouped, subtypes can be clearly separated by their sequence, conformation and, most importantly, their function.

Role in the immune system and apoptosis

Selectins, a group of proteins that are involved in leukocyte rolling towards a source of inflammation, contain an EGF-like domain along with a lectin domain and short consensus repeats (SCRs). [8] [9] The functions of the EGF-like domain vary between different selectin types. Kansas and co-workers were able to show that the EGF-like domain is not required for maximal cellular adhesion in L-selectin (expressed on lymphocytes). However, it is involved in both ligand recognition and adhesion in P-selectin (expressed on platelets) and may also be involved in protein-protein interactions. It has been suggested that the interactions between lectin domains and carbohydrate ligands might be calcium-dependent. [8]

Immature human dendritic cells appear to require interactions with the EGF-like domains of selectins during their maturation process. Blocking of this interaction with monoclonal anti-EGF-like domain antibodies prevents dendritic cell maturation. The immature cells fail to activate T-cells and produce less interleukin 12 than wild-type dendritic cells. [10]

Phan et al. could show that the artificial insertion of an N-glycosylation site into the EGF-like domains in P- and L-selectins increased the affinities of selectins to their ligands and led to slower rolling. [9] Therefore, EGF-like domains seem to play a crucial role in leukocyte movements towards inflammatory stimuli.

The EGF-like domain is also part of laminins, an important group of extracellular proteins. The EGF-like domains are usually masked in intact membranes, but become exposed when the membrane is destroyed, e.g. during inflammation, thereby stimulating membrane growth and restoring damaged membrane parts. [11]

Moreover, the EGF-like domain repeats of the stabilin-2 domain have been shown to specifically recognize and bind apoptotic cells, probably by recognizing phosphatidylserine, an apoptotic cell marker (“eat me-signal”). [12] Park et al. further demonstrated that the domains are able to competitively impair recognition of apoptotic cells by macrophages.

In conclusion, the EGF-like domain appears to play a vital role in immune responses as well as in eliminating dead cells in the organism.

Calcium-binding

Calcium-binding EGF-like domains (cbEGF-like domains) play a seminal role in diseases such as the Marfan syndrome [13] or the X-chromosome linked hemorrhagic disorder hemophilia B [14] and are among the most abundant extracellular calcium-binding domains. [15] Importantly, cbEGF- like domains impart specific functions to a variety of proteins in the blood clotting cascade. Examples include the coagulation factors VII, IX and X, protein C and its cofactor protein S. [15]

Calcium-binding EGF-like domains are typically composed of 45 amino acids, arranged as two antiparallel beta sheets. [15] Several cysteine residues within this sequence form disulfide bridges.

cbEGF-like domains show no significant structural deviations from EGF-like domains; however, as the name suggests, cbEGF-like domains bind a single calcium ion. The binding affinity to calcium varies widely and often depends on adjacent domains. [15] The consensus motif for calcium binding is Asp-Leu/Ile-Asp-Gln-Cys. Coordination of calcium strongly correlates with an unusual posttranslational modification of cbEGF-like domains: either an asparagine or aspartate is beta-hydroxylated giving rise to erythro-beta-hydroxyasparagine (Hyn) or erythro-beta-hydroxyaspartic acid (Hya), respectively. Hya can be found in the N-terminal cbEGF module (see below) of factors IX, X, and protein C. The Hyn modification appears to be more prevalent than Hya and has been shown to occur in fibrillin-1, an extracellular matrix protein. [16] Both modifications are catalyzed by the dioxygenase Asp/Asn-beta-hydroxylase, [17] and are unique to EGF domains in eukaryotes. [15]

Further posttranslational modifications have been reported. Glycosylation in the form of O-linked di- or trisaccharides may occur at a serine residue between the first two cysteines of blood coagulation factors VII and IX. [18] [19] [20] Factor VII exhibits an O-linked fucose at Ser60. [20]

Multiple cbEGF domains are often connected by one or two amino acids to form larger, repetitive arrays, here referred to as 'cbEGF modules'. In the blood-clotting cascade, coagulation factors VII, IX and X and protein C contain a tandem of two cbEGF modules, whereas protein S has four. Impressively, in fibrillin-1 and fibrillin-2, 43 cbEGF modules have been found. [21] The modularity of these proteins adds complexity to protein-protein but also module-module interaction. In factors VII, IX and X, the two cbEGF modules are preceded by an N-terminal gamma-carboxyglutamic acid (Gla) containing module (the Gla module). [15] In vitro studies on the Gla-cbEGF tandem isolated from factor X revealed a Kd-value of 0.1 mM for calcium binding [18] with the free calcium blood plasma concentrations being approximately 1.2 mM. Surprisingly, in the absence of the Gla module, the cbEGF module exhibits a Kd-value of 2.2 mM for calcium. [17] Thus, the presence of the Gla module increases calcium affinity 20-fold. Similarly, the activity of Gla and serine protease modules are modified by the cbEGF modules. In the absence of calcium, the Gla and cbEGF modules are highly mobile. As the cbEGF module associates with calcium, however, movement of the Gla module is significantly restricted because the cbEGF module now adopts a conformation that locks the neighboring Gla module in a fixed position. [22] [23] Therefore, calcium coordination induces conformational changes which, in turn, might modulate enzymatic activity.

Impaired coordination of calcium can result in serious disorders. Defective calcium binding to coagulation factor IX contributes to the development of hemophilia B. Individuals with this hereditary disease tend to develop hemorrhages, potentially leading to life-threatening conditions. The cause of hemophilia B is decreased activity or deficiency of blood coagulation factor IX. Point mutations resulting in decreased affinity of factor IX to calcium are thought to be implicated in this bleeding disorder. [15] On a molecular basis, it appears that hemophilia B can be the result of an impaired ability to localize the Gla module efficiently, as it usually occurs after calcium coordination by the cbEGF module in fully functional factor IX. [15] This defect is thought to impair the biological function of factor IX. A similar problem occurs in patients with hemophilia B and carrying a mutation (Glu78Lys) in factor IX that prevents interaction of the two cbEGF modules with one another. [15] Conversely, in healthy individuals, Glu78 in the first cbEGF-module contacts Arg94 in the second cbEGF module and thereby aligns both modules. [24] Thus, domain-domain interactions (partially facilitated by calcium coordination) are crucial for the catalytic activity of proteins involved in the blood-clotting cascade.

Proteins containing this domain

Below is a list of human proteins containing the EGF-like domain:

See also

Related Research Articles

<span class="mw-page-title-main">Carboxyglutamic acid</span> Chemical compound

Carboxyglutamic acid, is an uncommon amino acid introduced into proteins by a post-translational carboxylation of glutamic acid residues. This modification is found, for example, in clotting factors and other proteins of the coagulation cascade. This modification introduces an affinity for calcium ions. In the blood coagulation cascade, vitamin K is required to introduce γ-carboxylation of clotting factors II, VII, IX, X and protein Z.

<span class="mw-page-title-main">Epidermal growth factor</span> Protein that stimulates cell division and differentiation

Epidermal growth factor (EGF) is a protein that stimulates cell growth and differentiation by binding to its receptor, EGFR. Human EGF is 6-kDa and has 53 amino acid residues and three intramolecular disulfide bonds.

Factor IX Protein involved in blood clotting in humans

Factor IX is one of the serine proteases of the coagulation system; it belongs to peptidase family S1. Deficiency of this protein causes haemophilia B. It was discovered in 1952 after a young boy named Stephen Christmas was found to be lacking this exact factor, leading to haemophilia.

<span class="mw-page-title-main">Protein S</span>

Protein S is a vitamin K-dependent plasma glycoprotein synthesized in the liver. In the circulation, Protein S exists in two forms: a free form and a complex form bound to complement protein C4b-binding protein (C4BP). In humans, protein S is encoded by the PROS1 gene. Protein S plays a role in coagulation.

Fibrillin Protein family

Fibrillin is a glycoprotein, which is essential for the formation of elastic fibers found in connective tissue. Fibrillin is secreted into the extracellular matrix by fibroblasts and becomes incorporated into the insoluble microfibrils, which appear to provide a scaffold for deposition of elastin.

<span class="mw-page-title-main">Versican</span>

Versican is a large extracellular matrix proteoglycan that is present in a variety of human tissues. It is encoded by the VCAN gene.

Low-density lipoprotein receptor gene family

The low-density lipoprotein receptor gene family codes for a class of structurally related cell surface receptors that fulfill diverse biological functions in different organs, tissues, and cell types. The role that is most commonly associated with this evolutionarily ancient family is cholesterol homeostasis. In humans, excess cholesterol in the blood is captured by low-density lipoprotein (LDL) and removed by the liver via endocytosis of the LDL receptor. Recent evidence indicates that the members of the LDL receptor gene family are active in the cell signalling pathways between specialized cells in many, if not all, multicellular organisms.

Receptor tyrosine kinase Class of enzymes

Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins. Receptor tyrosine kinases have been shown not only to be key regulators of normal cellular processes but also to have a critical role in the development and progression of many types of cancer. Mutations in receptor tyrosine kinases lead to activation of a series of signalling cascades which have numerous effects on protein expression. Receptor tyrosine kinases are part of the larger family of protein tyrosine kinases, encompassing the receptor tyrosine kinase proteins which contain a transmembrane domain, as well as the non-receptor tyrosine kinases which do not possess transmembrane domains.

<span class="mw-page-title-main">Fibulin</span>

Fibulin (FY-beau-lin) is the prototypic member of a multigene family, currently with seven members. Fibulin-1 is a calcium-binding glycoprotein. In vertebrates, fibulin-1 is found in blood and extracellular matrices. In the extracellular matrix, fibulin-1 associates with basement membranes and elastic fibers. The association with these matrix structures is mediated by its ability to interact with numerous extracellular matrix constituents including fibronectin, proteoglycans, laminins and tropoelastin. In blood, fibulin-1 binds to fibrinogen and incorporates into clots.

Wall-associated kinase

Wall-associated kinases (WAKs) are one of many classes of plant proteins known to serve as a medium between the extracellular matrix (ECM) and cytoplasm of cell walls. They are serine-threonine kinases that contain epidermal growth factor (EGF) repeats, a cytoplasmic kinase and are located in the cell walls. They provide a linkage between the inner and outer surroundings of cell walls. WAKs are under a group of receptor-like kinases (RLK) that are actively involved in sensory and signal transduction pathways especially in response to foreign attacks by pathogens and in cell development. On the other hand, pectins are an abundant group of complex carbohydrates present in the primary cell wall that play roles in cell growth and development, protection, plant structure and water holding capacity.

<span class="mw-page-title-main">Fibrillin-1</span>

Fibrillin-1 is a protein that in humans is encoded by the FBN1 gene, located on chromosome 15. It is a large, extracellular matrix glycoprotein that serves as a structural component of 10-12 nm calcium-binding microfibrils. These microfibrils provide force bearing structural support in elastic and nonelastic connective tissue throughout the body. Mutations altering the protein can result in a variety of phenotypic effects differing widely in their severity, including fetal death, developmental problems, Marfan syndrome or in some cases Weill-Marchesani syndrome.

Discoidin domain

Discoidin domain is major protein domain of many blood coagulation factors.

<span class="mw-page-title-main">LTBP1 (gene)</span>

Latent-transforming growth factor beta-binding protein 1 is a protein that in humans is encoded by the LTBP1 gene.

LTBP3

Latent-transforming growth factor beta-binding protein 3 is a protein that in humans is encoded by the LTBP3 gene.

EFEMP2

EGF-containing fibulin-like extracellular matrix protein 2 is a protein that in humans is encoded by the EFEMP2 gene.

LTBP2

Latent-transforming growth factor beta-binding protein 2 is a protein that in humans is encoded by the LTBP2 gene.

Calcium-binding EGF domain

In molecular biology, the calcium-binding EGF domain is an EGF-like domain of about forty amino-acid residues found in epidermal growth factor (EGF). This domain is present in a large number of membrane-bound and extracellular, mostly animal, proteins. Many of these proteins require calcium for their biological function and a calcium-binding site has been found at the N-terminus of some EGF-like domains. Calcium-binding may be crucial for numerous protein-protein interactions.

SNED1 is an extracellular matrix (ECM) protein expressed at low levels in a wide range of tissues. The gene encoding SNED1 is located in the human chromosome 2 at locus q37.3. The corresponding mRNA isolated from the spleen and is 6834bp in length, and the corresponding protein is 1413 amino-acid long. The mouse ortholog of SNED1 was cloned in 2004 from the embryonic kidney by Leimester et al. SNED1 present domains characteristic of ECM proteins, including an amino-terminal NIDO domain, several calcium binding EGF-like domains (EGF_CA), a Sushi domain also known as complement control protein (CCP) domain, and three type III fibronectin (FN3) domains in the carboxy-terminal region.

Multiple Epidermal Growth Factor-like Domains 8 Protein-coding gene in the species Homo sapiens

Megf8 also known as Multiple Epidermal Growth Factor-like Domains 8, is a protein coding gene that encodes a single pass membrane protein, known to participate in developmental regulation and cellular communication. It is located on chromosome 19 at the 49th open reading frame in humans (19q13.2). There are two isoform constructs known for MEGF8, which differ by a 67 amino acid indel. The isoform 2 splice version is 2785 amino acids long, and predicted to be 296.6 kdal in mass. Isoform 1 is composed of 2845 amino acids and predicted to weigh 303.1 kdal. Using BLAST searches, orthologs were found primarily in mammals, but MEGF8 is also conserved in invertebrates and fishes, and rarely in birds, reptiles, and amphibians. A notably important paralog to multiple epidermal growth factor-like domains 8 is ATRNL1, which is also a single pass transmembrane protein, with several of the same key features and motifs as MEGF8, as indicated by Simple Modular Architecture Research Tool (SMART) which is hosted by the European Molecular Biology Laboratory located in Heidelberg, Germany. MEGF8 has been predicted to be a key player in several developmental processes, such as left-right patterning and limb formation. Currently, researchers have found MEGF8 SNP mutations to be the cause of Carpenter syndrome subtype 2.

3-Hydroxyasparagine Chemical compound

3-Hydroxyasparagine also known as β-hydroxyasparagine (beta-hydroxyasparagine) is a modified asparagine amino acid. It appears in posttranslational modification of cbEGF-like domains which can occur in humans and other Eukaryotes. The amino acid code used for this is Hyn. The modified amino acid residue is found in fibrillin-1. This amino acid is also found in urine.

References

  1. ↑ Nagata K, Kohda D, Hatanaka H, et al. (August 1994). "Solution structure of the epidermal growth factor-like domain of heregulin-alpha, a ligand for p180erbB-4". EMBO J. 13 (15): 3517–23. doi:10.1002/j.1460-2075.1994.tb06658.x. PMC   395255 . PMID   8062828.
  2. ↑ Downing AK, Knott V, Werner JM, Cardy CM, Campbell ID, Handford PA (May 1996). "Solution structure of a pair of calcium-binding epidermal growth factor-like domains: implications for the Marfan syndrome and other genetic disorders". Cell. 85 (4): 597–605. doi: 10.1016/S0092-8674(00)81259-3 . PMID   8653794. S2CID   15410014.
  3. ↑ Bork P, Downing AK, Kieffer B, Campbell ID (May 1996). "Structure and distribution of modules in extracellular proteins". Q. Rev. Biophys. 29 (2): 119–67. doi:10.1017/S0033583500005783. PMID   8870072. S2CID   6104446.
  4. 1 2 3 4 5 6 7 Wouters MA, Rigoutsos I, Chu CK, Feng LL, Sparrow DB, Dunwoodie SL (2005). "Evolution of distinct EGF domains with specific functions". Protein Science. 14 (4): 1091–103. doi:10.1110/ps.041207005. PMC   2253431 . PMID   15772310.
  5. 1 2 Bersch B, Hernandez JF, Marion D, Arlaud GJ (1998). "Solution Structure of the Epidermal Growth Factor (EGF)-like Module of Human Complement Protease C1r, an Atypical Member of the EGF Family". Biochemistry. 37 (5): 1204–14. doi:10.1021/bi971851v. PMID   9477945.
  6. ↑ Circolo A, Garnier G, Volanakis JE (2003). "A novel murine complement-related gene encoding a C1r-like serum protein". Molecular Immunology. 39 (14): 899–906. doi:10.1016/S0161-5890(02)00283-3. PMID   12686506.
  7. ↑ Stenflo J, Ohlin AK, Owen WG, Schneider WJ (1988). "beta-Hydroxyaspartic acid or beta-hydroxyasparagine in bovine low density lipoprotein receptor and in bovine thrombomodulin". Journal of Biological Chemistry. 263 (1): 21–24. doi: 10.1016/S0021-9258(19)57350-1 . PMID   2826439.
  8. 1 2 Kansas GS, Saunders KB, Ley K, et al. (1994). "A role for the epidermal growth factor-like domain of P-selectin in ligand recognition and cell adhesion". J Cell Biol. 124 (4): 609–18. doi:10.1083/jcb.124.4.609. PMC   2119911 . PMID   7508943.
  9. 1 2 Phan UT, Waldron TT, Springer TA (2006). "Remodeling of the lectin-EGF-like domain interface in P- and L-selectin increases adhesiveness and shear resistance under hydrodynamic force". Nat Immunol. 7 (8): 883–9. doi:10.1038/ni1366. PMC   1764822 . PMID   16845394.
  10. ↑ Zhou T, Zhang Y, Sun G, et al. (2006). "Anti-P-selectin lectin-EGF domain monoclonal antibody inhibits the maturation of human immature dendritic cells". Exp Mol Pathol. 80 (2): 171–6. doi:10.1016/j.yexmp.2005.10.004. PMID   16413535.
  11. ↑ Löffler, G; Petrides, PE; Heinrich, PC (1997). Biochemie und Pathobiochemie (5th ed.). Berlin, Heidelberg: Springer-Verlag. p. 747. ISBN   3-540-59006-4.
  12. ↑ Park SY, Kim SY, Jung MY, et al. (2008). "Epidermal growth factor-like domain repeat of tabilin-2 recognizes phosphatidylserine during cell corpse clearance". Mol Cell Biol. 28 (17): 5288–98. doi:10.1128/MCB.01993-07. PMC   2519725 . PMID   18573870.
  13. ↑ Handford PA, Downing AK, Rao Z, Hewett DR, Sykes BC, Kielty CM (1991). "The calcium binding properties and molecular organization of epidermal growth factor-like domains in human fibrillin-1". J. Biol. Chem. 270 (12): 6751–6. doi: 10.1074/jbc.270.12.6751 . PMID   7896820.
  14. ↑ Handford PA, Mayhew M, Baron M, Winship PR, Campbell ID, Brownlee GG (1991). "Key residues involved in calcium-binding motifs in EGF-like domains". Nature. 351 (6322): 164–7. Bibcode:1991Natur.351..164H. doi:10.1038/351164a0. PMID   2030732. S2CID   4338236.
  15. 1 2 3 4 5 6 7 8 9 Stenflo J, Stenberg Y, Muranyi A (2000). "Calcium-binding EGF-like modules in coagulation proteinases: function of the calcium ion in module interactions". Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology. 1477 (1–2): 51–63. doi:10.1016/s0167-4838(99)00262-9. PMID   10708848.
  16. ↑ Glanville RW, Qian RQ, McClure DW, Maslen CL, et al. (1994). "Calcium binding, hydroxylation, and glycosylation of the precursor epidermal growth factor-like domains of fibrillin-1, the Marfan gene protein". J. Biol. Chem. 269 (43): 26630–4. doi: 10.1016/S0021-9258(18)47065-2 . PMID   7929395.
  17. 1 2 Jia S, VanDusen WJ, Diehl RE, et al. (1992). "cDNA Cloning and Expression of Bovine Aspartyl (Asparaginyl) Beta-Hydroxylase". J. Biol. Chem. 267 (20): 14322–7. doi: 10.1016/S0021-9258(19)49715-9 . PMID   1378441.
  18. 1 2 Valcarce C, Selander-Sunnerhagen M, Tämlitz AM, Drakenberg T, Björk I, Stenflo J (1996). "Calcium Affinity of the NH2-terminal Epidermal Growth Factor-like Module of Factor X". J. Biol. Chem. 268 (35): 26673–8. doi: 10.1016/S0021-9258(19)74365-8 . PMID   8253800.
  19. ↑ Nishimura H, Kawabata S, Kisiel W, et al. (1989). "Identification of a disaccharide (Xyl-Glc) and a trisaccharide (Xyl2-Glc) O-glycosidically linked to a serine residue in the first epidermal growth factor-like domain of human factors VII and IX and protein Z and bovine protein Z". J. Biol. Chem. 264 (34): 20320–5. doi: 10.1016/S0021-9258(19)47065-8 . PMID   2511201.
  20. 1 2 Bjoern S, Foster D, Thim L, et al. (1991). "Human Plasma and Recombinant Factor VII". J. Biol. Chem. 266 (17): 11051–7. doi: 10.1016/S0021-9258(18)99126-X . PMID   1904059.
  21. ↑ Piha-Gossack A, Sossin W, Reinhardt DT, et al. (2012). "The evolution of extracellular fibrillins and their functional domains". PLOS ONE. 7 (3): 33560. Bibcode:2012PLoSO...733560P. doi: 10.1371/journal.pone.0033560 . PMC   3306419 . PMID   22438950.
  22. ↑ Sunnerhagen M, Forsen S, Hoffren A, Drakenberg T, Teleman O, Stenflo J (1995). "Structure of the Ca(2+)-free Gla domain sheds light on membrane binding of blood coagulation proteins". Nature Structural & Molecular Biology. 2 (6): 504–9. doi:10.1038/nsb0695-504. PMID   7664114. S2CID   8570806.
  23. ↑ Sunnerhagen M, Olah GA, Stenflo J, Forsen S, Drakenberg T, Trewhella J (1996). "The relative orientation of Gla and EGF domains in coagulation factor X is altered by Ca2+ binding to the first EGF domain. A combined NMR-small angle X-ray scattering study". Biochemistry. 35 (36): 11547–59. doi:10.1021/bi960633j. PMID   8794734.
  24. ↑ Christophe OD, Lenting PJ, Kolkman JA, Brownlee GG, Mertens K (1988). "Blood coagulation factor IX residues Glu78 and Arg94 provide a link between both epidermal growth factor-like domains that is crucial in the interaction with factor VIII light chain". J. Biol. Chem. 273 (1): 222–27. doi: 10.1074/jbc.273.1.222 . PMID   9417068.
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