Crystal structure of tandem type III fiibronectin domains from drosophila neuroglian at 2.0 å

Huber, Andrew H.; Wang, Yu mei Eureka; Bieber, Allan J.; Björkman, Pamela J.

doi:10.1016/0896-6273(94)90326-3

Cited by 105 publications

(92 citation statements)

References 43 publications

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“…1B). Of the structurally characterized Ig-like folds, only a few have a similar disulfide bond, including CD2 domain 2 (25) and the first fibronectin III repeat of neuroglian (26).…”

Section: Resultsmentioning

confidence: 99%

Antigen presentation subverted: Structure of the human cytomegalovirus protein US2 bound to the class I molecule HLA-A2

Gewurz

Gaudet

Tortorella

et al. 2001

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

139

134

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Many persistent viruses have evolved the ability to subvert MHC class I antigen presentation. Indeed, human cytomegalovirus (HCMV) encodes at least four proteins that down-regulate cellsurface expression of class I. The HCMV unique short (US)2 glycoprotein binds newly synthesized class I molecules within the endoplasmic reticulum (ER) and subsequently targets them for proteasomal degradation. We report the crystal structure of US2 bound to the HLA-A2͞Tax peptide complex. US2 associates with HLA-A2 at the junction of the peptide-binding region and the ␣3 domain, a novel binding surface on class I that allows US2 to bind independently of peptide sequence. Mutation of class I heavy chains confirms the importance of this binding site in vivo. Available data on class I-ER chaperone interactions indicate that chaperones would not impede US2 binding. Unexpectedly, the US2 ER-luminal domain forms an Ig-like fold. A US2 structure-based sequence alignment reveals that seven HCMV proteins, at least three of which function in immune evasion, share the same fold as US2. The structure allows design of further experiments to determine how US2 targets class I molecules for degradation.

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“…1B). Of the structurally characterized Ig-like folds, only a few have a similar disulfide bond, including CD2 domain 2 (25) and the first fibronectin III repeat of neuroglian (26).…”

Section: Resultsmentioning

confidence: 99%

Antigen presentation subverted: Structure of the human cytomegalovirus protein US2 bound to the class I molecule HLA-A2

Gewurz

Gaudet

Tortorella

et al. 2001

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

139

134

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“…FRET remaining at 2 M Gdn⅐HCl would then occur mainly between donors and acceptors in close proximity along the strands. High-resolution structures of FnIII modules have shown that different modules are structurally homologous and measure 3.2 nm from N to C terminus (22)(23)(24)(25). Because FRET is limited to donors and acceptors located within 10 nm of each other (26), only donors within modules FnIII 5-9 and FnIII [13][14][15] are sufficiently close to acceptors located within FnIII 7 and FnIII 15 to permit energy transfer.…”

Section: Discussionmentioning

confidence: 99%

Fibronectin extension and unfolding within cell matrix fibrils controlled by cytoskeletal tension

Baneyx

Baugh

Vogel

2002

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

333

306

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Evidence is emerging that mechanical stretching can alter the functional states of proteins. Fibronectin (Fn) is a large, extracellular matrix protein that is assembled by cells into elastic fibrils and subjected to contractile forces. Assembly into fibrils coincides with expression of biological recognition sites that are buried in Fn's soluble state. To investigate how supramolecular assembly of Fn into fibrillar matrix enables cells to mechanically regulate its structure, we used fluorescence resonance energy transfer (FRET) as an indicator of Fn conformation in the fibrillar matrix of NIH 3T3 fibroblasts. Fn was randomly labeled on amine residues with donor fluorophores and site-specifically labeled on cysteine residues in modules FnIII7 and FnIII15 with acceptor fluorophores. Intramolecular FRET was correlated with known structural changes of Fn in denaturing solution, then applied in cell culture as an indicator of Fn conformation within the matrix fibrils of NIH 3T3 fibroblasts. Based on the level of FRET, Fn in many fibrils was stretched by cells so that its dimer arms were extended and at least one FnIII module unfolded. When cytoskeletal tension was disrupted using cytochalasin D, FRET increased, indicating refolding of Fn within fibrils. These results suggest that cell-generated force is required to maintain Fn in partially unfolded conformations. The results support a model of Fn fibril elasticity based on unraveling and refolding of FnIII modules. We also observed variation of FRET between and along single fibrils, indicating variation in the degree of unfolding of Fn in fibrils. Molecular mechanisms by which mechanical force can alter the structure of Fn, converting tensile forces into biochemical cues, are discussed. E xtracellular matrices (ECM) are complex supramolecular assemblies that control cell signaling and behavior. While many ECM proteins have been characterized, little is known about how matrix assembly alters their structure and confers functions not present in individual proteins. Less is known about mechanisms by which cell contractile forces applied to protein assemblies regulate protein function. Many ECM proteins, such as fibronectin (Fn), laminin, and thrombospondin, are large (Ͼ100 kDa), multifunctional proteins composed of repeating, structurally defined modules often less than 100 aa each. The multimodular structure may serve as a convenient way to integrate multiple functions in one molecule. For example, some modules carry cell adhesion sites, whereas others carry sites for binding other proteins and for self-assembly. Exposure of functional sites may be controlled by the organization of such sites in extracellular matrices, and by the application of force by cells (1-3). However, the molecular mechanisms regulating ECM protein assembly and the exposure of binding sites remain unclear.Fn is an ECM protein that undergoes cell-mediated assembly into insoluble, elastic fibrils. In blood and when secreted by cells such as fibroblasts, Fn exists as a soluble dimer. The two strand...

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“…On both measures, the models were comparable to the templates. For ProfileQD, the evaluation scores for the growth hormone receptors (de Vos et al, 1992) and Drosophila neuroglian (Huber et al, 1994) ranged from 69 to 81% (observed score/expected score) and for the models, values ranged from 63 to 79%. Similarly, when using ProsaII, the models scored slightly less well than the crystal structures overall, but were better than the experimental structures over considerable regions (Smith, 889 1996).…”

Section: Model Structural Evaluation and Refinementmentioning

confidence: 99%

“…Models using both positions for the second disulfide bridge were constructed and evaluated to test whether this novel disulfide arrangement was more probable in LIFR. (Leahy et al., 1992); Drosophila neuroglian, lCFB (Huber et al, 1994); tissue factor, 2HFT (Muller et at., 1994)], and these were examined as part of the alignment process and for structural similarity. It was found that, when the coordinates of these FnIlI domains were superimposed, as shown in Figure 2, they had RMSD values ranging from 0.6 A to I .9 A, with an average of 1.2 A over the core B, C, E, and F strands (Smith, 1996).…”

Section: E L 8 D --~G T a H T I T D A Y A --G K E Y I 1~6 A A ~O Nmentioning

confidence: 99%

LIF receptor‐gp130 interaction investigated by homology modeling: Implications for LIF binding

Smith

Treutlein

1998

Protein Science

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Leukemia inhibitory factor (LIF), a member of the gp130 family of helical cytokines, is involved in the hemopoietic and neural systems. The LIF signal transducing complex contains two receptor molecules, the LIF receptor (LIFR) and gp130. The extracellular region of the LIFR is unique in that it includes three membrane-proximal fibronectin type 111 domains and two cytokine binding domains (CBDs) separated by an immunoglobulin-like domain. Although some mutagenesis data on LIF are available, it is not yet known which regions of LIFR or gp130 bind LIF. Nor is it known whether LIFR contacts gp130 in a manner similar to the growth hormone receptor dimer and, if so, through which of its CBDs. To attempt to elucidate these matters and to investigate the receptor complex, models of the CBDs of LIFR and the CBD of gp130 were constructed. Analyses of the electrostatic isopotential surfaces of the CBD models suggest that gp130 and the membrane-proximal CBD of LIFR hetero-dimerize and bind LIF through contacts similar to those seen in the growth hormone receptor dimer. This work further demonstrates the utility of electrostatic analyses of homology models and suggests a strategy for biochemical investigations of the LIF-receptor complex.

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Crystal structure of tandem type III fiibronectin domains from drosophila neuroglian at 2.0 å

Cited by 105 publications

References 43 publications

Antigen presentation subverted: Structure of the human cytomegalovirus protein US2 bound to the class I molecule HLA-A2

Antigen presentation subverted: Structure of the human cytomegalovirus protein US2 bound to the class I molecule HLA-A2

Fibronectin extension and unfolding within cell matrix fibrils controlled by cytoskeletal tension

LIF receptor‐gp130 interaction investigated by homology modeling: Implications for LIF binding

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