scholarly journals Structure-based alignment of human caspase recruitment domains provides a framework for understanding their function

2016 ◽  
Author(s):  
Joseph P. Boyle ◽  
Tom Monie
Keyword(s):  
Protein Interactions ◽  
Salt Bridge ◽  
Type I ◽  
Hydrophobic Core ◽  
Death Domain ◽  
Protein Protein Interactions ◽  
Sequence Alignments ◽  
And Function ◽  
Human Caspase ◽  
Death Domain Superfamily

AbstractIntracellular signalling is driven by protein-protein interactions. Members of the Death Domain superfamily mediate protein-protein interactions in both cell death and innate immune signalling pathways. They drive the formation of macromolecular complexes that act as a scaffold for protein recruitment and downstream signal transduction. Death Domain family members have low sequence identity, complicating their identification and predictions of their structure and function. We have taken all known human caspase recruitment domains (CARDs), a subfamily of the Death Domain superfamily, and generated a structure-guided sequence alignment. This alignment has enabled the identification of 14 positions that define the hydrophobic core and present a template for the identification of novel CARD sequences. We identify a conserved salt bridge in over half of all human CARDs and find a subset of CARDs likely to be regulated by tyrosine phosphorylation in their type I interface. Our alignment highlights that the CARDs of NLRC3 and NLRC5 are likely to be pseudodomains that have lost some of their original functionality. Together these studies demonstrate the benefits of structure-guided sequence alignments in understanding protein functionality.

scholarly journals Multiple Sequence Alignments as Tools for Protein Structure and Function Prediction

2003 ◽  
Vol 4 (4) ◽  
pp. 424-427 ◽  
Author(s):  
Alfonso Valencia
Keyword(s):  
Protein Structure ◽  
Protein Interactions ◽  
Protein Interaction Networks ◽  
Interaction Networks ◽  
Structure Evolution ◽  
Protein Protein Interactions ◽  
Sequence Alignments ◽  
Multiple Sequence ◽  
Multiple Sequence Alignments ◽  
And Function

Multiple sequence alignments have much to offer to the understanding of protein structure, evolution and function. We are developing approaches to use this information in predicting protein-binding specificity, intra-protein and protein-protein interactions, and in reconstructing protein interaction networks.

scholarly journals Short Linear Motifs Characterizing Snake Venom and Mammalian Phospholipases A2

Toxins ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 290
Author(s):  
Caterina Peggion ◽  
Fiorella Tonello
Keyword(s):  
Snake Venom ◽  
Protein Interactions ◽  
Biological Properties ◽  
Protein Protein Interactions ◽  
Sequence Alignments ◽  
Toxic Activity ◽  
Short Linear Motifs ◽  
Phospholipases A2 ◽  
Group I ◽  
Linear Motifs

Snake venom phospholipases A2 (PLA2s) have sequences and structures very similar to those of mammalian group I and II secretory PLA2s, but they possess many toxic properties, ranging from the inhibition of coagulation to the blockage of nerve transmission, and the induction of muscle necrosis. The biological properties of these proteins are not only due to their enzymatic activity, but also to protein–protein interactions which are still unidentified. Here, we compare sequence alignments of snake venom and mammalian PLA2s, grouped according to their structure and biological activity, looking for differences that can justify their different behavior. This bioinformatics analysis has evidenced three distinct regions, two central and one C-terminal, having amino acid compositions that distinguish the different categories of PLA2s. In these regions, we identified short linear motifs (SLiMs), peptide modules involved in protein–protein interactions, conserved in mammalian and not in snake venom PLA2s, or vice versa. The different content in the SLiMs of snake venom with respect to mammalian PLA2s may result in the formation of protein membrane complexes having a toxic activity, or in the formation of complexes whose activity cannot be blocked due to the lack of switches in the toxic PLA2s, as the motif recognized by the prolyl isomerase Pin1.

scholarly journals TRIM22. A Multitasking Antiviral Factor

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1864
Author(s):  
Isabel Pagani ◽  
Guido Poli ◽  
Elisa Vicenzi
Keyword(s):  
Protein Interactions ◽  
Influenza A ◽  
Direct Interaction ◽  
Type I Interferons ◽  
Viral Gene ◽  
Target Cells ◽  
Type I ◽  
Protein Protein Interactions ◽  
Viral Genomes ◽  
Dna And Rna

Viral invasion of target cells triggers an immediate intracellular host defense system aimed at preventing further propagation of the virus. Viral genomes or early products of viral replication are sensed by a number of pattern recognition receptors, leading to the synthesis and production of type I interferons (IFNs) that, in turn, activate a cascade of IFN-stimulated genes (ISGs) with antiviral functions. Among these, several members of the tripartite motif (TRIM) family are antiviral executors. This article will focus, in particular, on TRIM22 as an example of a multitarget antiviral member of the TRIM family. The antiviral activities of TRIM22 against different DNA and RNA viruses, particularly human immunodeficiency virus type 1 (HIV-1) and influenza A virus (IAV), will be discussed. TRIM22 restriction of virus replication can involve either direct interaction of TRIM22 E3 ubiquitin ligase activity with viral proteins, or indirect protein–protein interactions resulting in control of viral gene transcription, but also epigenetic effects exerted at the chromatin level.

scholarly journals Transactivation Functions of the N-Terminal Domains of Nuclear Hormone Receptors: Protein Folding and Coactivator Interactions

2003 ◽  
Vol 17 (1) ◽  
pp. 1-10 ◽  
Author(s):  
Raj Kumar ◽  
E. Brad Thompson
Keyword(s):  
Dna Binding ◽  
Protein Interactions ◽  
Hormone Receptors ◽  
Nuclear Hormone Receptor ◽  
Binding Domain ◽  
Dna Binding Domain ◽  
Protein Protein Interactions ◽  
Carboxy Terminal ◽  
And Function ◽  
Terminal Domains

Abstract The N-terminal domains (NTDs) of many members of the nuclear hormone receptor (NHR) family contain potent transcription-activating functions (AFs). Knowledge of the mechanisms of action of the NTD AFs has lagged, compared with that concerning other important domains of the NHRs. In part, this is because the NTD AFs appear to be unfolded when expressed as recombinant proteins. Recent studies have begun to shed light on the structure and function of the NTD AFs. Recombinant NTD AFs can be made to fold by application of certain osmolytes or when expressed in conjunction with a DNA-binding domain by binding that DNA-binding domain to a DNA response element. The sequence of the DNA binding site may affect the functional state of the AFs domain. If properly folded, NTD AFs can bind certain cofactors and primary transcription factors. Through these, and/or by direct interactions, the NTD AFs may interact with the AF2 domain in the ligand binding, carboxy-terminal portion of the NHRs. We propose models for the folding of the NTD AFs and their protein-protein interactions.

scholarly journals Multi-Omics Analysis Identifying Key Biomarkers in Ovarian Cancer

2020 ◽  
Vol 27 (1) ◽  
pp. 107327482097667
Author(s):  
Ju-Yueh Li ◽  
Chia-Jung Li ◽  
Li-Te Lin ◽  
Kuan-Hao Tsui
Keyword(s):  
Ovarian Cancer ◽  
Protein Interactions ◽  
Malignant Tumors ◽  
Single Gene ◽  
Protein Protein Interactions ◽  
Normal Tissues ◽  
Human Protein Atlas ◽  
Copy Number Changes ◽  
And Function ◽  
Cancer Tissues

Ovarian cancer is one of the most common malignant tumors. Here, we aimed to study the expression and function of the CREB1 gene in ovarian cancer via the bioinformatic analyses of multiple databases. Previously, the prognosis of ovarian cancer was based on single-factor or single-gene studies. In this study, different bioinformatics tools (such as TCGA, GEPIA, UALCAN, MEXPRESS, and Metascape) have been used to assess the expression and prognostic value of the CREB1 gene. We used the Reactome and cBioPortal databases to identify and analyze CREB1 mutations, copy number changes, expression changes, and protein–protein interactions. By analyzing data on the CREB1 differential expression in ovarian cancer tissues and normal tissues from 12 studies collected from the “Human Protein Atlas” database, we found a significantly higher expression of CREB1 in normal ovarian tissues. Using this database, we collected information on the expression of 25 different CREB-related proteins, including TP53, AKT1, and AKT3. The enrichment of these factors depended on tumor metabolism, invasion, proliferation, and survival. Individualized tumors based on gene therapy related to prognosis have become a new possibility. In summary, we established a new type of prognostic gene profile for ovarian cancer using the tools of bioinformatics.

scholarly journals Properties of the phage-shock-protein (Psp) regulatory complex that govern signal transduction and induction of the Psp response in Escherichia coli

Microbiology ◽  
2010 ◽  
Vol 156 (10) ◽  
pp. 2920-2932 ◽  
Author(s):  
Goran Jovanovic ◽  
Christoph Engl ◽  
Antony J. Mayhew ◽  
Patricia C. Burrows ◽  
Martin Buck
Keyword(s):  
Escherichia Coli ◽  
Signal Transduction ◽  
Protein Interactions ◽  
Leucine Zipper ◽  
Negative Control ◽  
Stress Conditions ◽  
Bacterial Cells ◽  
Protein Protein Interactions ◽  
Regulatory Complex ◽  
And Function

The phage-shock-protein (Psp) response maintains the proton-motive force (pmf) under extracytoplasmic stress conditions that impair the inner membrane (IM) in bacterial cells. In Escherichia coli transcription of the pspABCDE and pspG genes requires activation of σ 54-RNA polymerase by the enhancer-binding protein PspF. A regulatory network comprising PspF–A–C–B–ArcB controls psp expression. One key regulatory point is the negative control of PspF imposed by its binding to PspA. It has been proposed that under stress conditions, the IM-bound sensors PspB and PspC receive and transduce the signal(s) to PspA via protein–protein interactions, resulting in the release of the PspA–PspF inhibitory complex and the consequent induction of psp. In this work we demonstrate that PspB self-associates and interacts with PspC via putative IM regions. We present evidence suggesting that PspC has two topologies and that conserved residue G48 and the putative leucine zipper motif are determinants required for PspA interaction and signal transduction upon stress. We also establish that PspC directly interacts with the effector PspG, and show that PspG self-associates. These results are discussed in the context of formation and function of the Psp regulatory complex.

scholarly journals Distinct activities of Scrib module proteins organize epithelial polarity

2020 ◽  
Vol 117 (21) ◽  
pp. 11531-11540 ◽  
Author(s):  
Mark J. Khoury ◽  
David Bilder
Keyword(s):  
Protein Interactions ◽  
Molecular Mechanisms ◽  
Epithelial Polarity ◽  
Protein Protein Interactions ◽  
Kinase C ◽  
Mutual Antagonism ◽  
Discs Large ◽  
Lethal Giant Larvae ◽  
Epithelial Structure ◽  
And Function

A polarized architecture is central to both epithelial structure and function. In many cells, polarity involves mutual antagonism between the Par complex and the Scribble (Scrib) module. While molecular mechanisms underlying Par-mediated apical determination are well-understood, how Scrib module proteins specify the basolateral domain remains unknown. Here, we demonstrate dependent and independent activities of Scrib, Discs-large (Dlg), and Lethal giant larvae (Lgl) using theDrosophilafollicle epithelium. Our data support a linear hierarchy for localization, but rule out previously proposed protein–protein interactions as essential for polarization. Cortical recruitment of Scrib does not require palmitoylation or polar phospholipid binding but instead an independent cortically stabilizing activity of Dlg. Scrib and Dlg do not directly antagonize atypical protein kinase C (aPKC), but may instead restrict aPKC localization by enabling the aPKC-inhibiting activity of Lgl. Importantly, while Scrib, Dlg, and Lgl are each required, all three together are not sufficient to antagonize the Par complex. Our data demonstrate previously unappreciated diversity of function within the Scrib module and begin to define the elusive molecular functions of Scrib and Dlg.

scholarly journals Structure and function of human Vps20 and Snf7 proteins

2004 ◽  
Vol 377 (3) ◽  
pp. 693-700 ◽  
Author(s):  
Jeremy W. PECK ◽  
Emma T. BOWDEN ◽  
Peter D. BURBELO
Keyword(s):  
Protein Interactions ◽  
Osmotic Shock ◽  
Multivesicular Body ◽  
Protein Protein Interactions ◽  
Interacting Protein ◽  
Endosomal Membrane ◽  
Genomic Studies ◽  
Vacuolar Protein ◽  
And Function

Snf7p (sucrose non-fermenting) and Vps20p (vacuolar protein-sorting) are small coil-coiled proteins involved in yeast MVB (multivesicular body) structure, formation and function. In the present study, we report the identification of three human homologues of yeast Snf7p, designated hSnf7-1, hSnf7-2 and hSnf7-3, and a single human Vps20p homologue, designated hVps20, that may have similar roles in humans. Immunofluorescence studies showed that hSnf7-1 and hSnf7-3 localized in large vesicular structures that also co-localized with late endosomal/lysosomal structures induced by overexpressing an ATPase-defective Vps4-A mutant. In contrast, overexpressed hVps20 showed a typical endosomal membrane-staining pattern, and co-expression of hVps20 with Snf7-1 dispersed the large Snf7-staining vesicles. Interestingly, overexpression of both hSnf7 and hVps20 proteins induced a post-endosomal defect in cholesterol sorting. To explore possible protein–protein interactions involving hSnf7 proteins, we used information from yeast genomic studies showing that yeast Snf7p can interact with proteins involved in MVB function. Using a glutathione S-transferase-capture approach with several mammalian homologues of such yeast Snf7p-interacting proteins, we found that all three hSnf7s interacted with mouse AIP1 [ALG-2 (apoptosis-linked gene 2) interacting protein 1], a mammalian Bro1p [BCK1 (bypass of C kinase)-like resistance to osmotic shock]-containing protein involved in cellular vacuolization and apoptosis. Whereas mapping experiments showed that the N-terminus of AIP1 containing both a Bro1 and an α-helical domain were required for interaction with hSnf7-1, Snf7-1 did not interact with another human Bro1-containing molecule, rhophilin-2. Co-immunoprecipitation experiments confirmed the in vivo interaction of hSnf7-1 and AIP1. Additional immunofluorescence experiments showed that hSnf7-1 recruited cytosolic AIP1 to the Snf7-induced vacuolar-like structures. Together these results suggest that mammalian Vps20, AIP1 and Snf7 proteins, like their yeast counterparts, play roles in MVB function.

An activity-based probe reveals dynamic protein–protein interactions mediating IGF-1R transactivation by the GABAB receptor

2012 ◽  
Vol 443 (3) ◽  
pp. 627-634 ◽  
Author(s):  
Xin Lin ◽  
Xin Li ◽  
Ming Jiang ◽  
Linhai Chen ◽  
Chanjuan Xu ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Protein Complex ◽  
Tyrosine Kinases ◽  
Chemical Biology ◽  
Molecular Mechanisms ◽  
Gabab Receptor ◽  
Type I ◽  
Protein Protein Interactions ◽  
Downstream Effectors ◽  
Factor Type

Many GPCRs (G-protein-coupled receptors) can activate RTKs (receptor tyrosine kinases) in the absence of RTK ligands, a phenomenon called transactivation. However, the underlying molecular mechanisms remain undefined. In the present study we investigate the molecular basis of GABAB (γ-aminobutyric acid B) receptor-mediated transactivation of IGF-1R (insulin-like growth factor type I receptor) in primary neurons. We take a chemical biology approach by developing an activity-based probe targeting the GABAB receptor. This probe enables us first to lock the GABAB receptor in an inactive state and then activate it with a positive allosteric modulator, thereby permitting monitoring of the dynamic of the protein complex associated with IGF-1R transactivation. We find that activation of the GABAB receptor induces a dynamic assembly and disassembly of a protein complex, including both receptors and their downstream effectors. FAK (focal adhesion kinase), a non-RTK, plays a key role in co-ordinating this dynamic process. Importantly, this dynamic of the GABAB receptor-associated complex is critical for transactivation and transactivation-dependent neuronal survival. The present study has identified an important mechanism underlying GPCR transactivation of RTKs, which was enabled by a new chemical biology tool generally applicable for dissecting GPCR signalling.

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