Structural Model and trans-Interaction of the Entire Ectodomain of the Olfactory Cell Adhesion Molecule

Kulahin, Nikolaj; Kristensen, Ole; Rasmussen, Kim Krighaar; Olsen, Lars Arnskov; Rydberg, Patrik; Vestergaard, Bente; Kastrup, J.S.; Berezin, Vladimir; Bock, Elisabeth; Walmod, Peter S.; Gajhede, Michael

doi:10.1016/j.str.2010.12.014

Cited by 27 publications

(25 citation statements)

References 62 publications

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“…Overall, this analysis demonstrates that the L-shaped conformation adopted by this fragment of CNTN3 mirrors its conformation in solution. Taken together, these findings indicate that the FN regions of CNTNs all adopt a bent conformation reminiscent of the one adopted by NCAM2 (25).…”

Section: Identification Of a Ptprg⅐cntn Complex In Adult Mousementioning

confidence: 64%

Structural Basis for Interactions Between Contactin Family Members and Protein-tyrosine Phosphatase Receptor Type G in Neural Tissues

Nikolaienko

Hammel

Dubreuil

et al. 2016

Journal of Biological Chemistry

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Protein-tyrosine phosphatase receptor type G (RPTP␥/ PTPRG) interacts in vitro with contactin-3-6 (CNTN3-6), a group of glycophosphatidylinositol-anchored cell adhesion molecules involved in the wiring of the nervous system. In addition to PTPRG, CNTNs associate with multiple transmembrane proteins and signal inside the cell via cis-binding partners to alleviate the absence of an intracellular region. Here, we use comprehensive biochemical and structural analyses to demonstrate that PTPRG⅐CNTN3-6 complexes share similar binding affinities and a conserved arrangement. Furthermore, as a first step to identifying PTPRG⅐CNTN complexes in vivo, we found that PTPRG and CNTN3 associate in the outer segments of mouse rod photoreceptor cells. In particular, PTPRG and CNTN3 form cis-complexes at the surface of photoreceptors yet interact in trans when expressed on the surfaces of apposing cells. Further structural analyses suggest that all CNTN ectodomains adopt a bent conformation and might lie parallel to the cell surface to accommodate these cis and trans binding modes. Taken together, these studies identify a PTPRG⅐CNTN complex in vivo and provide novel insights into PTPRG-and CNTN-mediated signaling.The complex processes that shape the nervous system include the proliferation, differentiation, and migration of neural cells, axon guidance, and the formation of synapses. At the molecular level, these intricate processes rely on interactions between cell surface receptors coupled to intracellular downstream signaling networks. Such receptors might include cadherins, Ig superfamily proteins, neurexins, neuroligins, and leucine-rich repeat proteins as well as receptor tyrosine kinases and receptor protein-tyrosine phosphatases (RPTPs) 4 (1, 2). Members of the RPTP family typically combine large extracellular segments and intracellular phosphatase domains, which makes them ideally suited to coordinate cell adhesion and cell signaling. Among these, the homologous protein-tyrosine phosphatase receptor type G (PTPRG) and protein-tyrosine phosphatase receptor type Z (PTPRZ) were among the first RPTPs identified in the nervous system, and their ectodomains are characterized by the presence of an inactive N-terminal carbonic anhydrase-like (CA) domain that mediates proteinprotein interactions (Fig. 1A) (3, 4). PTPRZ and its binding partner, the neural cell adhesion molecule contactin-1 (CNTN1), control the proliferation of oligodendrocyte precursor cells and their maturation into myelinating oligodendrocytes (5). Less is known, however, about PTPRG, its in vivo ligands, and the physiological roles these complexes might play.Unlike PTPRZ, PTPRG is mostly expressed on neurons, although it has recently been found in some astrocytes and microglia in adult mouse brains (4, 6). PTPRG interacts in vitro via its CA domain with four homologs of CNTN1 called CNTN3-6 (7). All CNTNs are linked to the membrane by a glycophosphatidylinositol (GPI) anchor, suggesting that they require a co-receptor to signal across the membrane (8, 9). CNTNs a...

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Section: Identification Of a Ptprg⅐cntn Complex In Adult Mousementioning

confidence: 64%

Structural Basis for Interactions Between Contactin Family Members and Protein-tyrosine Phosphatase Receptor Type G in Neural Tissues

Nikolaienko

Hammel

Dubreuil

et al. 2016

Journal of Biological Chemistry

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“…It adopts a typical Ig-like fold, structurally most closely homologous to the FNIII domains of receptor tyrosine phosphatase μ (RPTPμ) and neural cell adhesion molecule 2 (NCAM2) (16,17). The association between Ig3 and FNIII-1 is inflexible, which facilitates the overall rigid elongated molecular architecture of the Tie2 ectodomain.…”

Section: Resultsmentioning

confidence: 99%

Structural basis for angiopoietin-1–mediated signaling initiation

Seegar

Dalton

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Angiogenesis is a complex cellular process involving multiple regulatory growth factors and growth factor receptors. Among them, the ligands for the endothelial-specific tunica intima endothelial receptor tyrosine kinase 2 (Tie2) receptor kinase, angiopoietin-1 (Ang1) and Ang2, play essential roles in balancing vessel stability and regression during both developmental and tumorinduced angiogenesis. Despite possessing a high degree of sequence identity, Ang1 and Ang2 have distinct functional roles and cellsignaling characteristics. Here, we present the crystal structures of Ang1 both unbound and in complex with the Tie2 ectodomain.Comparison of the Ang1-containing structures with their Ang2-containing counterparts provide insight into the mechanism of receptor activation and reveal molecular surfaces important for interactions with Tie2 coreceptors and associated signaling proteins. Using structure-based mutagenesis, we identify a loop within the angiopoietin P domain, adjacent to the receptor-binding interface, which confers the specific agonist/antagonist properties of the molecule. We demonstrate using cell-based assays that an Ang2 chimera containing the Ang1 loop sequence behaves functionally similarly to Ang1 as a constitutive Tie2 agonist, able to efficiently dissociate the inhibitory Tie1/Tie2 complex and elicit Tie2 clustering and downstream signaling. cellular signaling | Tie receptor tyrosine kinase | X-ray crystallography P roper development of the cardiovascular system involves two highly integrated and dynamic processes: vasculogenesis and angiogenesis (1). Vasculogenesis involves the in situ differentiation of endothelial cells from precursor angioblasts and results in their subsequent migration and proliferation, leading to the formation of the endocardium of the heart, as well as the major primitive blood vessels (2-6). Angiogenesis occurs following vasculogenesis and results in the remodeling and extension of the endothelial tubes into the adult microvasculature, as well as in the growth and expansion of vessels into organs including the kidney and brain. Endothelial cells lining these newly formed vessels are surrounded by support cells, such as smooth muscle cells and pericytes, which serve to regulate blood flow and provide survival signals (7). Angiogenesis predominantly takes place during embryonic development, although it also recurs during wound repair in adulthood. Its role is essential for tumor development, as well as metastasis and, therefore, represents a viable target for therapeutic intervention (8).The angiopoietins are a small set of growth factor ligands for the tunica intima endothelial receptor tyrosine kinase 2 (Tie2) endothelial-specific receptor tyrosine kinase and are critical for both development and pathological angiogenesis (9-11). The prototypic family member, angiopoietin-1 (Ang1), is a Tie2 agonist, whereas the highly homologous Ang2 is a context-dependent agonist/antagonist. All angiopoietin family members, Ang1 to -4, contain an amino-terminal "superclustering" and...

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“…3). A recent crystal structure of the human OCAM Ig4-Ig5-FN1-FN2 domains (Protein Data Bank entry 2JLL) revealed GlcNAc residues at only six of the eight potential N-linked glycosylation sites (42). Notably, the only sites where GlcNAc residues were not observed were the extra N-linked glycosylation sites on both Ig5 and FN1.…”

Section: Discussionmentioning

confidence: 99%

The Polysialyltransferases Interact with Sequences in Two Domains of the Neural Cell Adhesion Molecule to Allow Its Polysialylation

Thompson¹,

Foley²,

Colley

2013

Journal of Biological Chemistry

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Background: Recognition of the protein substrate is the first step in polysialylation of its glycans. Results: Residues in the OCAM Ig5 domain are non-permissive for its polysialylation. Conclusion:The polysialyltransferases interact with residues in both the Ig5 and FN1 domains of NCAM to allow its polysialylation. Significance: A two-domain polysialyltransferase recognition site may be required for all polysialylated proteins.

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Structural Model and trans-Interaction of the Entire Ectodomain of the Olfactory Cell Adhesion Molecule

Cited by 27 publications

References 62 publications

Structural Basis for Interactions Between Contactin Family Members and Protein-tyrosine Phosphatase Receptor Type G in Neural Tissues

Structural Basis for Interactions Between Contactin Family Members and Protein-tyrosine Phosphatase Receptor Type G in Neural Tissues

Structural basis for angiopoietin-1–mediated signaling initiation

The Polysialyltransferases Interact with Sequences in Two Domains of the Neural Cell Adhesion Molecule to Allow Its Polysialylation

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