The Crystal Structure of the Ligand Binding Module of Axonin-1/TAG-1 Suggests a Zipper Mechanism for Neural Cell Adhesion

Freigang, Jörg; Proba, Karl; Leder, Lukas; Diederichs, Kay; Sonderegger, P.; Welte, Wolfram

doi:10.1016/s0092-8674(00)80852-1

Cited by 163 publications

(194 citation statements)

References 34 publications

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“…1A). This domain arrangement has not been observed in previous multiFNIII repeat structures (23,24), but a similar arrangement has been observed for repeated Ig-like ␤-sandwich domains in axonin-1 (25) and hemolin (26).…”

Section: Resultssupporting

confidence: 83%

Structure of a heparin-dependent complex of Hedgehog and Ihog

McLellan¹,

Yao

Zheng

et al. 2006

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

146

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H edgehog (Hh) is a secreted signaling molecule that mediates key tissue-patterning events during both vertebrate and invertebrate development (1-3). Hh also plays an important role in the maintenance and regulation of stem cells in adult organisms (4, 5). Abnormal activation of the Hh signaling pathway has been implicated in the initiation and growth of many human tumors (6), and drugs targeting the Hh pathway are under development (7).Hh is secreted but undergoes two lipid modifications that restrict its free diffusion and facilitate transport to appropriate target sites (8,9). Hh binding to Ptc, a 12-pass integral membrane protein with homology to bacterial resistance-nodulationdivision (RND) transporters (10) is a central event in Hh signaling and blocks the ability of Ptc to inhibit the seven-pass integral membrane protein Smoothened (Smo), a positive regulator of Hh responses (10). Recent genetic and RNAi experiments implicate the membrane-associated proteins Ihog and dally-like protein (Dlp) in Hh responsiveness (11)(12)(13)(14). Dlp, a member of the glypican family of heparan sulfate proteoglycans (HSPGs) (15), has dual roles in mediating Hh responsiveness and in transport of the Hh signal to distant cells (12)(13)(14). Heparan sulfate glycosaminoglycan chains, in particular, have also been implicated in Hh movement by the observation that tout velu, which encodes a heparan sulfate copolymerase (16, 17) that acts on Dlp (12), is required for normal Hh transport.Ihog, a Drosophila protein previously known as CG9211, is a type I transmembrane protein with four Ig domains followed by two FNIII domains, a membrane-spanning region, and a cytoplasmic region of no known function (11). Ihog is homologous to another Drosophila protein, CG32796 or brother of Ihog (BOI), and two mammalian proteins, CDO and BOC (18,19), that are also components of the Hh signaling pathway (11,20,21). Several observations indicate that Ihog may function as a coreceptor for Hh: (i) reduction of Ihog expression results in diminished Hh binding and responsiveness, (ii) epistasis experiments place Ihog function upstream or at the level of Ptc, (iii) the Ihog extracellular region is able to pull down HhN from conditioned medium, and (iv) coexpression of Ptc and Ihog results in a synergistic increase in Hh binding to the cell surface (11).The first FNIII domain of Ihog (IhogFn1) is necessary and sufficient to pull down HhN, but both FNIII domains are needed to synergize with Ptc and reconstitute Ihog function in cell-based signaling assays (11). Complicating interpretation of Ihog function is the observation that purified HhN and Ihog extracellular regions do not appreciably interact (see Fig. 2 A), indicating that a binary interaction between Ihog and Hh cannot explain Ihog function. To investigate the role of Ihog in Hh signaling, we initiated structural and biophysical studies of functional fragments of Drosophila melanogaster Ihog and Hh. Results and DiscussionStructure of Ihog FNIII Domains. The crystal structure of IhogFn1 was determ...

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Section: Resultssupporting

confidence: 83%

Structure of a heparin-dependent complex of Hedgehog and Ihog

McLellan¹,

Yao

Zheng

et al. 2006

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

146

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“…We next used these agents to locate binding sites on hL1 Ig1-4, an appropriately sized protein for tandem MS (MS/MS) identification of photolabeled peptides and the smallest fragment of L1 that exhibits homophilic binding (22,27). To minimize nonspecific binding, we photolabeled at decreasing concentrations until little photoincorporation could be detected.…”

Section: Resultsmentioning

confidence: 99%

“…To better appreciate the location of these sites, we constructed a homology model of residues 33-424 of hL1 Ig1-4 based on axonin Ig1-4, the largest fragment of any L1 superfamily member to be crystallized to date (27). In the Ramachandran plot of the model shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

An alcohol binding site on the neural cell adhesion molecule L1

Arevalo

Shanmugasundararaj

Wilkemeyer

et al. 2008

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

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“…The insertion of 4 amino acids between Ig1 and Ig2 completely abrogated bead binding. The inserted sequence of small, relatively hydrophilic residues was designed to introduce significant conformational freedom between the Ig domains, while not facilitating the type of intramolecular interactions seen in L1/axonin-1 (31,32). The sequence was inserted between Lys 98 and Leu 99 , the two residues identified in the crystal structure as a linker between Ig1 and Ig2 (19).…”

Section: Discussionmentioning

confidence: 99%