Crystal Structure of a C-terminal Fragment of Growth Arrest-specific Protein Gas6

Sasaki, Takako; Knyazev, Pjotr; Cheburkin, Yuri; Göhring, Walter; Tisi, Dominic; Ullrich, Axel; Timpl, Rupert; Hohenester, Erhard

doi:10.1074/jbc.m207340200

Cited by 83 publications

(82 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There are several calcium-binding sites within the Gla, EGF-like, and SHBG domains of PROS1 and GAS6 that may contribute to the ligand activity (39,40). Crystal structures of TAM domains also revealed the interaction between Ni 2ϩ , Zn 2ϩ , Ca 2ϩ…”

Section: Resultsmentioning

confidence: 99%

Receptor Tyrosine Kinases, TYRO3, AXL, and MER, Demonstrate Distinct Patterns and Complex Regulation of Ligand-induced Activation

Tsou

Nguyen²,

Calarese³

et al. 2014

Journal of Biological Chemistry

191

203

View full text Add to dashboard Cite

Background:The mechanisms by which ligands activate TAM receptors (TYRO3, AXL, and MER) are not well understood. Results:We created a series of TAM reporter cell lines and interrogated ligand-inducible TAM activation. Conclusion: TAMs are differentially activated by GAS6 and protein S and have distinct requirements for phosphatidylserine. Significance: Results reveal molecular mechanisms and rationale for non-overlapping functions of TAMs.

show abstract

Section: Resultsmentioning

confidence: 99%

Receptor Tyrosine Kinases, TYRO3, AXL, and MER, Demonstrate Distinct Patterns and Complex Regulation of Ligand-induced Activation

Tsou

Nguyen²,

Calarese³

et al. 2014

Journal of Biological Chemistry

191

203

View full text Add to dashboard Cite

show abstract

“…1). This SHBG-like module is both necessary and sufficient for TAM receptor binding and activation, whereas the Gla domain is dispensable for these activities 7,18 . Overall, GAS6 and protein S sharẽ 42% amino-acid identity.…”

Section: Tam Receptors and Ligandsmentioning

confidence: 99%

Immunobiology of the TAM receptors

2008

View full text Add to dashboard Cite

Recent studies have revealed that the TAM receptor protein tyrosine kinases -TYRO3, AXL and MER -have pivotal roles in innate immunity. They inhibit inflammation in dendritic cells and macrophages, promote the phagocytosis of apoptotic cells and membranous organelles, and stimulate the maturation of natural killer cells. Each of these phenomena may depend on a cooperative interaction between TAM receptor and cytokine receptor signalling systems. Although its importance was previously unrecognized, TAM signalling promises to have an increasingly prominent role in studies of innate immune regulation.Receptor protein tyrosine kinases (PTKs) are cell-surface transmembrane receptors that contain a regulated PTK activity within their cytoplasmic domains. They function as sensors for extracellular ligands, the binding of which triggers receptor dimerization and activation of the receptor's kinase. This leads to the recruitment, phosphorylation and activation of multiple downstream signalling proteins, which ultimately change the physiology of cells. Although there are only 58 receptor PTK genes in the human genome 1 (see the human kinome website), the signal transduction cascades initiated by receptor PTK activation control diverse cellular processes -from cell differentiation to cell death. Well-known receptor PTK subfamilies include the ERBB receptors, which have essential roles in cardiac and neural development and the progression of some forms of breast cancer 2 ; and the ephrin receptors, which are required for tissue morphogenesis and the patterning of neuronal connections in the developing brain 3 .The focus of this Review, the TAM group, was among the last receptor PTK subfamilies to be identified, and the biological roles of its three members -TYRO3, AXL and MERremained uncharacterized for several years. Largely through the analysis of engineered lossof-function mutants in mice, these roles have become increasingly apparent. They reflect a specific requirement for TAM signalling in settings in which fully differentiated cells, tissues and organs must be maintained in the face of continuous challenge, turnover and renewal. In humans, ongoing homeostatic regulation of this sort must be carried out, frequently on a daily basis, for decades. Although an essential role for TAM regulation of tissue homeostasis is evident in the adult nervous, reproductive and vascular systems, it is in In this Review, we highlight the central roles that TAM signalling has in the intrinsic inhibition of the inflammatory response to pathogens by dendritic cells (DCs) and macrophages; during phagocytosis of apoptotic cells by these same cells; and in the maturation and killing activity of natural killer (NK) cells. We also discuss how, in many or all of these settings, TAM receptors depend on and interact with cytokine receptors. TAM receptors and ligandsThe three TAM receptors, TYRO3, AXL and MER, were identified as a distinct receptor PTK subfamily in 1991 (REFS 4,5 ). Subsequent cloning of full-length cDNAs by multiple labo...

show abstract

“…In addition to TSPN-1 and several glycolytic enzymes, the top hits include serum amyloid P component (28), neurexin 1␤ (22), calnexin (24), laminin G-like domain (LG5; Ref. 20), agrin G3 domain (26), Gas6 (25), and SHBG (21). These multifunctional protein domains, including TSPN-1, are involved in heparin, steroid ligand, and protein-protein interactions rather than in binding simple carbohydrates.…”

Section: Datamentioning

confidence: 99%

“…On the basis of amino acid sequence conservation and the apparent similarities of the secondary structural elements, it was predicted that the TSPN module is homologous with pentraxins and with members of the lamininneurexin-sex hormone binding globulin (LNS) domain family (18,19). Three-dimensional structures of LNS modules from the laminin ␣2 chain (␣2LG5) (20), sex hormone binding globulin (SHBG) (21), neurexins 1␤ (22) and 1␣ (23), calnexin (24), growth arrest-specific protein Gas6 (25), agrin (26), and the N-terminal domain of thrombospondin-1 (TSPN-1) (27) along with structures of the pentraxins serum amyloid P component (28) and C-reactive protein (29,30) are now available. All members of the superfamily share a ␤-sandwich fold with a convex and a concave sheet, each comprised of six or seven antiparallel ␤-strands.…”

mentioning

confidence: 99%

Crystal Structure of the N-terminal NC4 Domain of Collagen IX, a Zinc Binding Member of the Laminin-Neurexin-Sex Hormone Binding Globulin (LNS) Domain Family

Leppänen

Tossavainen

Permi

et al. 2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

Collagen IX, located on the surface of collagen fibrils, is crucial for cartilage integrity and stability. The N-terminal NC4 domain of the ␣1(IX) chain is probably important in this because it interacts with various macromolecules such as proteoglycans and cartilage oligomeric matrix protein. At least 17 distinct collagen polypeptides carry an NC4-like unit near their N terminus, but this report, describing the crystal structure of NC4 at 1.8-Å resolution, represents the first atomic level structure for these domains. The structure is similar to previously characterized laminin-neurexin-sex hormone binding globulin (LNS) structures, dominated by an antiparallel ␤-sheet sandwich. In addition, a zinc ion was found in a position similar to that of the metal binding site of other LNS domains. A partial backbone NMR assignment of NC4 was obtained and utilized in NMR titration studies to investigate the zinc binding in solution state and to quantitate the affinity of metal binding. The K d of 11.5 mM suggests a regulatory rather than a structural role for zinc in solution. NMR titration with a heparin tetrasaccharide revealed the presence of a secondary binding site for heparin on NC4, showing structural and functional conservation with thrombospondin-1, but a markedly reduced affinity for the ligand. Also the overall arrangement of the N and C termini of NC4 resembles most closely the N-terminal domain of thrombospondin-1, distinguishing the two from the majority of the published LNS structures.Collagens are a family of extracellular matrix proteins comprised of at least 28 distinct types, all characterized by the presence of one or more elongated triple helical regions. This common motif is supplemented with a variety of non-helical domains to add unique properties for molecular or supramolecular assembly, for tissue-specific targeting, or for interactions with other constituents of the matrix (1, 2). An example of such a supplementary element is a module showing similarity to the N-terminal domains of thrombospondins (TSPNs) 2 (3). This domain occurs in at least 17 different collagen polypeptides, located N-terminal to the triple helix, but little is known about the detailed structures and physiological functions of these units (2).One of the TSPNs found in collagen chains is the NC4 domain of collagen IX, formed by about 245 N-terminal residues of the mature ␣1(IX) polypeptide. In cartilage tissue, collagen IX molecules are covalently bound to the heteropolymeric collagen fibrils that provide the tissue with high tensile strength to resist the swelling pressure caused by proteoglycans. The shorter arm of the triple helix of collagen IX projects away from the fibril body so that the NC4 domain can easily interact with other macromolecules. The temporal and spatial control over the presence or absence of NC4 on collagen IX via alternative splicing (4, 5) suggests that the domain has functional significance. The NC4 domain, as well as three other regions along the collagen IX triple helix, has been shown to interact...

show abstract

Crystal Structure of a C-terminal Fragment of Growth Arrest-specific Protein Gas6

Cited by 83 publications

References 47 publications

Receptor Tyrosine Kinases, TYRO3, AXL, and MER, Demonstrate Distinct Patterns and Complex Regulation of Ligand-induced Activation

Receptor Tyrosine Kinases, TYRO3, AXL, and MER, Demonstrate Distinct Patterns and Complex Regulation of Ligand-induced Activation

Immunobiology of the TAM receptors

Crystal Structure of the N-terminal NC4 Domain of Collagen IX, a Zinc Binding Member of the Laminin-Neurexin-Sex Hormone Binding Globulin (LNS) Domain Family

Contact Info

Product

Resources

About