scholarly journals Dynamic catch of a Thy-1–α5β1+syndecan-4 trimolecular complex

2014 ◽  
Vol 5 (1) ◽  
Author(s):  
Vincent F. Fiore ◽  
Lining Ju ◽  
Yunfeng Chen ◽  
Cheng Zhu ◽  
Thomas H. Barker
Keyword(s):  
Trimolecular Complex

scholarly journals Type 1 diabetes: primary antigen/peptide/register/trimolecular complex

2012 ◽  
Vol 55 (1-3) ◽  
pp. 270-276 ◽  
Author(s):  
Tomasz Sosinowski ◽  
George S. Eisenbarth
Keyword(s):  
Type 1 Diabetes ◽  
Antigen Peptide ◽  
Trimolecular Complex

scholarly journals Deletion of the Thrombin Proteolytic Site in Neurofascin 155 Causes Disruption of Nodal and Paranodal Organization

2021 ◽  
Vol 15 ◽  
Author(s):  
Dipankar J. Dutta ◽  
R. Douglas Fields
Keyword(s):  
Nervous System ◽  
Gene Editing ◽  
Cell Types ◽  
Complete Loss ◽  
Spectrometric Analysis ◽  
The Third ◽  
Proteolytic Site ◽  
The Central Nervous System ◽  
Trimolecular Complex ◽  
Unique Domain

In the central nervous system, myelin is attached to the axon in the paranodal region by a trimolecular complex of Neurofascin155 (NF155) in the myelin membrane, interacting with Caspr1 and Contactin1 on the axolemma. Alternative splicing of a single Neurofascin transcript generates several different Neurofascins expressed by several cell types, but NF155, which is expressed by oligodendrocytes, contains a domain in the third fibronectinIII-like region of the molecule that is unique. The immunoglobulin 5–6 domain of NF155 is essential for binding to Contactin1, but less is known about the functions of the NF155-unique third fibronectinIII-like domain. Mutations and autoantibodies to this region are associated with several neurodevelopmental and demyelinating nervous system disorders. Here we used Crispr-Cas9 gene editing to delete a 9 bp sequence of NF155 in this unique domain, which has recently been identified as a thrombin binding site and implicated in plasticity of the myelin sheath. This small deletion results in dysmyelination, eversion of paranodal loops of myelin, substantial enlargement of the nodal gap, a complete loss of paranodal septate junctions, and mislocalization of Caspr1 and nodal sodium channels. The animals exhibit tremor and ataxia, and biochemical and mass spectrometric analysis indicates that while NF155 is transcribed and spliced normally, the NF155 protein is subsequently degraded, resulting in loss of the full length 155 kDa native protein. These findings reveal that this 9 bp region of NF155 in its unique third fibronectinIII-like domain is essential for stability of the protein.

scholarly journals Pentosan polysulfate increases affinity between ADAMTS-5 and TIMP-3 through formation of an electrostatically driven trimolecular complex

2012 ◽  
Vol 443 (1) ◽  
pp. 307-315 ◽  
Author(s):  
Linda Troeberg ◽  
Barbara Mulloy ◽  
Peter Ghosh ◽  
Meng-Huee Lee ◽  
Gillian Murphy ◽  
...  
Keyword(s):  
Sulfated Polysaccharide ◽  
Pentosan Polysulfate ◽  
Endogenous Inhibitor ◽  
Binding Ability ◽  
Physiological Conditions ◽  
Interaction Sites ◽  
High Affinity ◽  
Multiple Protein ◽  
Trimolecular Complex ◽  
Protein Interaction Sites

The semi-synthetic sulfated polysaccharide PPS (pentosan polysulfate) increases affinity between the aggrecan-degrading ADAMTSs (adamalysins with thrombospondin motifs) and their endogenous inhibitor, TIMP (tissue inhibitor of metalloproteinases)-3. In the present study we demonstrate that PPS mediates the formation of a high-affinity trimolecular complex with ADAMTS-5 and TIMP-3. A TIMP-3 mutant that lacks extracellular-matrix-binding ability was insensitive to this affinity increase, and truncated forms of ADAMTS-5 that lack the Sp (spacer) domain had reduced PPS-binding ability and sensitivity to the affinity increase. PPS molecules composed of 11 or more saccharide units were 100-fold more effective than those of eight saccharide units, indicating the involvement of extended or multiple protein-interaction sites. The formation of a high-affinity trimolecular complex was completely abolished in the presence of 0.4 M NaCl. These results suggest that PPS enhances the affinity between ADAMTS-5 and TIMP-3 by forming electrostatically driven trimolecular complexes under physiological conditions.

scholarly journals Targeting the trimolecular complex

2013 ◽  
Vol 149 (3) ◽  
pp. 339-344 ◽  
Author(s):  
Aaron W. Michels
Keyword(s):  
Trimolecular Complex

scholarly journals Activation of the classical pathway of complement by Hageman factor fragment.

1981 ◽  
Vol 153 (3) ◽  
pp. 665-676 ◽  
Author(s):  
B Ghebrehiwet ◽  
M Silverberg ◽  
A P Kaplan
Keyword(s):  
Normal Serum ◽  
Classical Pathway ◽  
Hageman Factor ◽  
Concomitant Reduction ◽  
Dose Dependent Fashion ◽  
Total Complement ◽  
Trimolecular Complex ◽  
Comparable Activity ◽  
The Individual ◽  
Antigen Antibody

A fragment of activated Hageman factor (HFf) has been demonstrated to activate the classical pathway of complement in a manner that is analogous to complement activation by antigen-antibody complexes or aggregated IgG. Thus C1, C4, C2, C3, and C5 were found to be depleted on addition of HFf to serum. The reduction of serum hemolytic activity was maximal upon addition of 5 micrograms HFf and an incubation time of 60 min at 37 degrees C. Consumption of the total complement activity and of the individual components proceeded in a dose-dependent fashion. No comparable activity was observed when equimolar concentrations of either the native Hageman factor (HF) or two-chain activated form of Hageman factor (HFa) were incubated with serum. Further, the ability of HFf to convert serum C3 and C4 was similar to that of aggregated IgG as assessed by immunoelectrophoresis. This function of HFf appeared to be independent of plasminogen (or plasmin) since plasminogen-free serum was indistinguishable from normal serum. Radial double immunodiffusion experiments using antiserum to C1q, C1r, and C1s on HFf-treated serum demonstrated the dissociation of the C1 trimolecular complex, with concomitant reduction of C1r antigenicity that is indicative of C1 activation. Thus, HFf appears to lead to C1 activation upon incubation with serum or when incubated with partially purified C1. This may represent a control link between activation of the intrinsic coagulation-kinin pathway and the initiation of the classical complement cascade.

SLP-76-Cbl-Grb2-Shc Interactions in FcγRI Signaling

Blood ◽  
1998 ◽  
Vol 92 (5) ◽  
pp. 1697-1706 ◽  
Author(s):  
Julie Chu ◽  
Yenbou Liu ◽  
Gary A. Koretzky ◽  
Donald L. Durden
Keyword(s):  
Adapter Proteins ◽  
Adapter Protein ◽  
Nucleotide Exchange ◽  
Receptor Stimulation ◽  
Receptor Aggregation ◽  
Intracellular Signals ◽  
Trimolecular Complex ◽  
American Society ◽  
Activation Motif

Abstract SLP-76 and Cbl are complex adapter proteins that have the capacity to bind to smaller adapter proteins, such as Grb2, which subsequently binds the nucleotide exchange protein Sos in the transmission of intracellular signals. SLP-76, Cbl, Shc, and Grb2 have been implicated in immunoreceptor tyrosine-based activation motif (ITAM) signaling, leading to activation of Ras. However, their mechanism of action has not been determined. To date, there have been no reports of SLP-76 involvement in FcγRI-receptor signaling and no data exist for an interaction between Cbl, Shc, and SLP-76 in vivo. We provide evidence that SLP-76, Cbl, and Shc are tyrosine phosphorylated on FcγRI-receptor stimulation and are associated with the adapter protein Grb2 in γ-interferon–differentiated U937 cells (U937IF). The interactions between SLP-76 and Cbl and SLP-76 and Grb2 are present in resting U937IF cells. However, the interaction between SLP-76 and Grb2 becomes augmented twofold on FcγRI-receptor aggregation. Our results provide the first evidence for a phosphorylation-dependent interaction between SLP-76 and Shc, induced at least 10-fold on FcγRI receptor stimulation. Our data indicate that a significant portion of a multimolecular complex containing Cbl, SLP-76, Shc, and Grb2 is distinct from a trimolecular complex containing the Ras guanine nucleotide exchanger Sos, Shc, and Grb2. FcγRI-induced tyrosine phosphorylation of SLP-76, Cbl, Shc, and the highly induced SLP-76-Shc interaction provide the first evidence that SLP-76 and Cbl are involved in FcγRI signaling and suggest a functional significance for these interactions in FcγRI signal relay in the control of Ras in myeloid cells. © 1998 by The American Society of Hematology.

SLP-76-Cbl-Grb2-Shc Interactions in FcγRI Signaling

Blood ◽  
1998 ◽  
Vol 92 (5) ◽  
pp. 1697-1706 ◽  
Author(s):  
Julie Chu ◽  
Yenbou Liu ◽  
Gary A. Koretzky ◽  
Donald L. Durden
Keyword(s):  
Adapter Proteins ◽  
Adapter Protein ◽  
Nucleotide Exchange ◽  
Receptor Stimulation ◽  
Receptor Aggregation ◽  
Intracellular Signals ◽  
Trimolecular Complex ◽  
American Society ◽  
Activation Motif

SLP-76 and Cbl are complex adapter proteins that have the capacity to bind to smaller adapter proteins, such as Grb2, which subsequently binds the nucleotide exchange protein Sos in the transmission of intracellular signals. SLP-76, Cbl, Shc, and Grb2 have been implicated in immunoreceptor tyrosine-based activation motif (ITAM) signaling, leading to activation of Ras. However, their mechanism of action has not been determined. To date, there have been no reports of SLP-76 involvement in FcγRI-receptor signaling and no data exist for an interaction between Cbl, Shc, and SLP-76 in vivo. We provide evidence that SLP-76, Cbl, and Shc are tyrosine phosphorylated on FcγRI-receptor stimulation and are associated with the adapter protein Grb2 in γ-interferon–differentiated U937 cells (U937IF). The interactions between SLP-76 and Cbl and SLP-76 and Grb2 are present in resting U937IF cells. However, the interaction between SLP-76 and Grb2 becomes augmented twofold on FcγRI-receptor aggregation. Our results provide the first evidence for a phosphorylation-dependent interaction between SLP-76 and Shc, induced at least 10-fold on FcγRI receptor stimulation. Our data indicate that a significant portion of a multimolecular complex containing Cbl, SLP-76, Shc, and Grb2 is distinct from a trimolecular complex containing the Ras guanine nucleotide exchanger Sos, Shc, and Grb2. FcγRI-induced tyrosine phosphorylation of SLP-76, Cbl, Shc, and the highly induced SLP-76-Shc interaction provide the first evidence that SLP-76 and Cbl are involved in FcγRI signaling and suggest a functional significance for these interactions in FcγRI signal relay in the control of Ras in myeloid cells. © 1998 by The American Society of Hematology.

scholarly journals Activation of Vav by the Gammaherpesvirus M2 Protein Contributes to the Establishment of Viral Latency in B Lymphocytes

2006 ◽  
Vol 80 (12) ◽  
pp. 6123-6135 ◽  
Author(s):  
Lénia Rodrigues ◽  
Marta Pires de Miranda ◽  
María J. Caloca ◽  
Xosé R. Bustelo ◽  
J. Pedro Simas
Keyword(s):  
B Lymphocytes ◽  
Viral Latency ◽  
Murine Gammaherpesvirus ◽  
Host Interaction ◽  
New Type ◽  
Trimolecular Complex ◽  
Gammaherpesvirus 68 ◽  
Novel Strategy ◽  
Murine Gammaherpesvirus 68

ABSTRACT Gammaherpesviruses subvert eukaryotic signaling pathways to favor latent infections in their cellular reservoirs. To this end, they express proteins that regulate or replace functionally specific signaling proteins of eukaryotic cells. Here we describe a new type of such viral-host interaction that is established through M2, a protein encoded by murine gammaherpesvirus 68. M2 associates with Vav proteins, a family of phosphorylation-dependent Rho/Rac exchange factors that play critical roles in lymphocyte signaling. M2 expression leads to Vav1 hyperphosphorylation and to the subsequent stimulation of its exchange activity towards Rac1, a process mediated by the formation of a trimolecular complex with Src kinases. This heteromolecular complex is coordinated by proline-rich and Src family-dependent phosphorylated regions of M2. Infection of Vav-deficient mice with gammaherpesvirus 68 results in increased long-term levels of latency in germinal center B lymphocytes, corroborating the importance of the M2/Vav cross talk in the process of viral latency. These results reveal a novel strategy used by the murine gammaherpesvirus family to subvert the lymphocyte signaling machinery to its own benefit.

scholarly journals Two Distinct Tyrosine-based Motifs Enable the Inhibitory Receptor FcγRIIB to Cooperatively Recruit the Inositol Phosphatases SHIP1/2 and the Adapters Grb2/Grap

2004 ◽  
Vol 279 (50) ◽  
pp. 51931-51938 ◽  
Author(s):  
Isabelle Isnardi ◽  
Renaud Lesourne ◽  
Pierre Bruhns ◽  
Wolf H. Fridman ◽  
John C. Cambier ◽  
...  
Keyword(s):  
Cell Activation ◽  
Sh2 Domain ◽  
Scaffold Proteins ◽  
Src Homology 2 ◽  
Dependent Cell ◽  
Trimolecular Complex ◽  
Src Homology ◽  
Inositol Phosphatases ◽  
Necessary And Sufficient ◽  
Activation Motif

FcγRIIB are low-affinity receptors for IgG that contain an immunoreceptor tyrosine-based inhibition motif (ITIM) and inhibit immunoreceptor tyrosine-based activation motif (ITAM)-dependent cell activation. When coaggregated with ITAM-bearing receptors, FcγRIIB become tyrosyl-phosphorylated and recruit the Src homology 2 (SH2) domain-containing inositol 5′-phosphatases SHIP1 and SHIP2, which mediate inhibition. The FcγRIIB ITIM was proposed to be necessary and sufficient for recruiting SHIP1/2. We show here that a second tyrosine-containing motif in the intracytoplasmic domain of FcγRIIB is required for SHIP1/2 to be coprecipitated with the receptor. This motif functions as a docking site for the SH2 domain-containing adapters Grb2 and Grap. These adapters interact via their C-terminal SH3 domain with SHIP1/2 to form a stable receptor-phosphatase-adapter trimolecular complex. Both Grb2 and Grap are required for an optimal coprecipitation of SHIP with FcγRIIB, but one adapter is sufficient for the phosphatase to coprecipitate in a detectable manner with the receptors. In addition to facilitating the recruitment of SHIPs, the second tyrosine-based motif may confer upon FcγRIIB the properties of scaffold proteins capable of altering the composition and stability of the signaling complexes generated following receptor engagement.

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