scholarly journals TWEAK binding to the Fn14 cysteine-rich domain depends on charged residues located in both the A1 and D2 modules

2006 ◽  
Vol 397 (2) ◽  
pp. 297-304 ◽  
Author(s):  
Sharron A. N. Brown ◽  
Heather N. Hanscom ◽  
Hong Vu ◽  
Shelesa A. Brew ◽  
Jeffrey A. Winkles
Keyword(s):  
Electrostatic Interactions ◽  
Homology Model ◽  
Amino Acid Residues ◽  
Binding Assays ◽  
High Affinity ◽  
Rich Domain ◽  
Biological Responses ◽  
Extracellular Region ◽  
Critical Residues ◽  
Cysteine Rich Domain

TWEAK [TNF (tumour necrosis factor)-like weak inducer of apoptosis] is a member of the TNF superfamily of cytokines. TWEAK binds with high affinity to a single TNF receptor super-family member, Fn14 (fibroblast growth factor-inducible 14). This interaction can stimulate a variety of biological responses, depending on the cell type analysed. The murine Fn14 extracellular region is only 53 amino acids in length and primarily consists of a CRD (cysteine-rich domain) containing three disulphide bonds. In the present study, we investigated whether TWEAK binding to this CRD was dependent on selected evolutionarily conserved amino acid residues by using a site-specific mutagenesis approach and several different ligand-binding assays. Our results indicate that three residues within the predicted Fn14 CRD A1 module (Asp45, Lys48 and Met50) and one residue within the predicted D2 module (Asp62) are each critical for high-affinity TWEAK binding. Mutation of the three charged polar residues Asp45, Lys48 and Asp62 had the greatest deleterious effect, suggesting that electrostatic interactions between TWEAK and Fn14 residues may be particularly important for complex formation or stability. To determine whether the four critical residues were likely to be located on the Fn14 CRD surface, we made an Fn14 homology model based on a previously derived X-ray structure for the B-cell maturation antigen receptor, which also contains only one CRD. This model revealed that each of these critical residues were in areas of the receptor that are potentially capable of interacting with TWEAK. These results indicate that the TWEAK–Fn14 interaction is highly dependent on multiple Fn14 residues located in both CRD modules.

scholarly journals Five amino acid residues in cysteine-rich domain of human T1R3 were involved in the response for sweet-tasting protein, thaumatin

Biochimie ◽  
2013 ◽  
Vol 95 (7) ◽  
pp. 1502-1505 ◽  
Author(s):  
Tetsuya Masuda ◽  
Wakana Taguchi ◽  
Ayane Sano ◽  
Keisuke Ohta ◽  
Naofumi Kitabatake ◽  
...  
Keyword(s):  
Amino Acid ◽  
Amino Acid Residues ◽  
Rich Domain ◽  
Cysteine Rich Domain

scholarly journals Cryo-EM structure of the activated RET signaling complex reveals the importance of its cysteine-rich domain

2019 ◽  
Vol 5 (7) ◽  
pp. eaau4202 ◽  
Author(s):  
Janna M. Bigalke ◽  
Shintaro Aibara ◽  
Robert Roth ◽  
Göran Dahl ◽  
Euan Gordon ◽  
...  
Keyword(s):  
Calcium Binding ◽  
Neurological Diseases ◽  
Receptor Activation ◽  
Loss Of Function ◽  
Calcium Binding Site ◽  
Signaling Complex ◽  
Rich Domain ◽  
Extracellular Region ◽  
Domain 3 ◽  
Cysteine Rich Domain

Signaling through the receptor tyrosine kinase RET is essential during normal development. Both gain- and loss-of-function mutations are involved in a variety of diseases, yet the molecular details of receptor activation have remained elusive. We have reconstituted the complete extracellular region of the RET signaling complex together with Neurturin (NRTN) and GFRα2 and determined its structure at 5.7-Å resolution by cryo-EM. The proteins form an assembly through RET-GFRα2 and RET-NRTN interfaces. Two key interaction points required for RET extracellular domain binding were observed: (i) the calcium-binding site in RET that contacts GFRα2 domain 3 and (ii) the RET cysteine-rich domain interaction with NRTN. The structure highlights the importance of the RET cysteine-rich domain and allows proposition of a model to explain how complex formation leads to RET receptor dimerization and its activation. This provides a framework for targeting RET activity and for further exploration of mechanisms underlying neurological diseases.

scholarly journals The Evolution of the Scavenger Receptor Cysteine-Rich Domain of the Class A Scavenger Receptors

2015 ◽  
Vol 6 ◽  
Author(s):  
Nicholas V. L. Yap ◽  
Fiona J. Whelan ◽  
Dawn M. E. Bowdish ◽  
G. Brian Golding
Keyword(s):  
Scavenger Receptor ◽  
Scavenger Receptors ◽  
Class A ◽  
Rich Domain ◽  
Cysteine Rich Domain

scholarly journals The unusual structure of the PiggyMac cysteine-rich domain reveals zinc finger diversity in PiggyBac-related transposases

Mobile DNA ◽  
2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Marc Guérineau ◽  
Luiza Bessa ◽  
Séverine Moriau ◽  
Ewen Lescop ◽  
François Bontems ◽  
...  
Keyword(s):  
Zinc Finger ◽  
Dna Cleavage ◽  
Trichoplusia Ni ◽  
Catalytic Domain ◽  
Structural Diversity ◽  
Paramecium Tetraurelia ◽  
Lysine Methylation ◽  
Unusual Structure ◽  
Rich Domain ◽  
Cysteine Rich Domain

Abstract Background Transposons are mobile genetic elements that colonize genomes and drive their plasticity in all organisms. DNA transposon-encoded transposases bind to the ends of their cognate transposons and catalyze their movement. In some cases, exaptation of transposon genes has allowed novel cellular functions to emerge. The PiggyMac (Pgm) endonuclease of the ciliate Paramecium tetraurelia is a domesticated transposase from the PiggyBac family. It carries a core catalytic domain typical of PiggyBac-related transposases and a short cysteine-rich domain (CRD), flanked by N- and C-terminal extensions. During sexual processes Pgm catalyzes programmed genome rearrangements (PGR) that eliminate ~ 30% of germline DNA from the somatic genome at each generation. How Pgm recognizes its DNA cleavage sites in chromatin is unclear and the structure-function relationships of its different domains have remained elusive. Results We provide insight into Pgm structure by determining the fold adopted by its CRD, an essential domain required for PGR. Using Nuclear Magnetic Resonance, we show that the Pgm CRD binds two Zn2+ ions and forms an unusual binuclear cross-brace zinc finger, with a circularly permutated treble-clef fold flanked by two flexible arms. The Pgm CRD structure clearly differs from that of several other PiggyBac-related transposases, among which is the well-studied PB transposase from Trichoplusia ni. Instead, the arrangement of cysteines and histidines in the primary sequence of the Pgm CRD resembles that of active transposases from piggyBac-like elements found in other species and of human PiggyBac-derived domesticated transposases. We show that, unlike the PB CRD, the Pgm CRD does not bind DNA. Instead, it interacts weakly with the N-terminus of histone H3, whatever its lysine methylation state. Conclusions The present study points to the structural diversity of the CRD among transposases from the PiggyBac family and their domesticated derivatives, and highlights the diverse interactions this domain may establish with chromatin, from sequence-specific DNA binding to contacts with histone tails. Our data suggest that the Pgm CRD fold, whose unusual arrangement of cysteines and histidines is found in all PiggyBac-related domesticated transposases from Paramecium and Tetrahymena, was already present in the ancestral active transposase that gave rise to ciliate domesticated proteins.

scholarly journals Mediation of interleukin-11-dependent biological responses by a soluble form of the interleukin-11 receptor

1996 ◽  
Vol 318 (2) ◽  
pp. 489-495 ◽  
Author(s):  
Julia KAROW ◽  
Keith R. HUDSON ◽  
Mark A. HALL ◽  
Ann B. VERNALLIS ◽  
Jacky A. TAYLOR ◽  
...  
Keyword(s):  
Biological Effects ◽  
Biological Response ◽  
Cytoplasmic Domain ◽  
Soluble Form ◽  
High Affinity ◽  
Biological Responses ◽  
Interleukin 11 ◽  
Biological Actions ◽  
In Cells

Interleukin-11 (IL-11) is a polyfunctional cytokine whose biological actions require a specific IL-11 receptor (IL-11R) and the transmembrane transducer gp130. Here we report the production of a soluble form of the murine IL-11R and demonstrate that it interacts with IL-11 ligand with high affinity. The affinity of IL-11 alone for gp130 is below the level of detection, but a complex of IL-11 and soluble IL-11R interacts with gp130 with high affinity. The addition of soluble IL-11R potentiates the effects of exogenous IL-11 in cells that are normally responsive to IL-11. A biological response to IL-11 can be reconstituted in BAF cells transfected with gp130 by addition of IL-11 and soluble IL-11R. These findings show that the cytoplasmic domain of the IL-11R is not required for the biological effects of IL-11 and that a complex of IL-11 and IL-11R mediates signalling by association with gp130.

scholarly journals Elucidation of Binding Determinants and Functional Consequences of Ras/Raf-Cysteine-rich Domain Interactions

2000 ◽  
Vol 275 (29) ◽  
pp. 22172-22179 ◽  
Author(s):  
Jason G. Williams ◽  
Jonelle K. Drugan ◽  
Gwan-Su Yi ◽  
Geoffrey J. Clark ◽  
Channing J. Der ◽  
...  
Keyword(s):  
Rich Domain ◽  
Domain Interactions ◽  
Functional Consequences ◽  
Binding Determinants ◽  
Cysteine Rich Domain

scholarly journals Structural Analysis of Yoked Chorionic Gonadotropin-Luteinizing Hormone Receptor Ectodomain Complexes by Circular Dichroic Spectroscopy

2003 ◽  
Vol 17 (7) ◽  
pp. 1192-1202 ◽  
Author(s):  
Gregory B. Fralish ◽  
Brian Dattilo ◽  
David Puett
Keyword(s):  
Chorionic Gonadotropin ◽  
Fusion Proteins ◽  
Homology Model ◽  
Difference Spectrum ◽  
Luteinizing Hormone Receptor ◽  
Amino Acid Residues ◽  
Single Chain ◽  
Glycoprotein Hormone ◽  
The Difference ◽  
Α Helix

Abstract Binding of the heterodimeric glycoprotein hormone, chorionic gonadotropin (CG), occurs to the heptahelical LH receptor N-terminal ectodomain (ECD), a large portion of which has been modeled as a leucine-rich repeat protein. In this study, we expressed and purified three single chain N-CG-ECD-C complexes, one comprising the full-length ECD, 1–341 (encoded by exons 1–10 and a portion of 11), and two C-terminal ECD deletion fragments, 1–294 (encoded by exons 1–10) and 1–180 (encoded by exons 1–7). The fusion proteins, including yoked CG (N-β-α-C), were characterized by Western blot analysis and circular dichroism (CD). Analysis of the CD spectra obtained on the CG-ECD fusion proteins, and of the difference spectrum of each after subtracting the CG contribution, yielded secondary structures consistent with a repeating β-strand/α-helix fold as predicted in the homology model. A marked decrease in helicity was observed when the C-terminal 47 amino acid residues were removed from the ECD. Removal of an additional 114 residues, i.e. the region encoded by exons 8–10, results in the loss of fewer helical residues. These results suggest that the hinge region of the ECD, predicted to contain only limited secondary structure, interacts with and stabilizes the ligand-occupied N-terminal portion. Furthermore, the results support a repeating fold, consistent with the proposed model for the LHR ECD.

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