Modulating the Bcl-2 Family of Apoptosis Suppressors for Potential Therapeutic Benefit in Cancer

Hematology ◽  
2005 ◽  
Vol 2005 (1) ◽  
pp. 226-230 ◽  
Author(s):  
Gordon C. Shore ◽  
Jean Viallet
Keyword(s):  
Protein Interactions ◽  
Therapeutic Benefit ◽  
Protein Protein Interactions ◽  
Cancer Treatments ◽  
The Family ◽  
Challenges And Opportunities ◽  
Apoptosis Pathways ◽  
Current Therapies ◽  
Cellular Oncogenes ◽  
Potential Therapeutic Benefit

Abstract Members of the BCL-2 family of proteins regulate and execute many cell intrinsic apoptosis pathways, including those arising from dysregulated expression of cellular oncogenes. Since pro-survival members of the family are often strongly elevated in diverse cancers, with the potential to confer resistance to both endogenous cell death stimuli and many cancer treatments, there has been intense interest to develop strategies to therapeutically modulate their activity. Although encouraging genetic and pharmacological preclinical proof of concept has been obtained, the challenge for clinical development will be to devise strategies that address the fact that multiple pro-survival members are typically up-regulated in a given cancer and the family operates primarily through protein-protein interactions. Moreover, since several current therapies themselves are known to stimulate the levels of one or more family members, there will be additional challenges (and opportunities) in exploiting this target in the clinic. In this review, we describe the rationale for targeting the BCL-2 family of apoptosis suppressors in cancer and the progress that has been made in modulating the family by small molecule antagonists.

Molecular Biology of Protein-Protein Interactions for Computer Scientists

2009 ◽  
pp. 1-13 ◽  
Author(s):  
Christian Schönbach
Keyword(s):  
Molecular Biology ◽  
Protein Interactions ◽  
Wnt Signaling Pathway ◽  
Protein Protein Interactions ◽  
Protein Protein Interaction ◽  
Ppi Networks ◽  
Detection Technology ◽  
Challenges And Opportunities ◽  
Computer Scientists ◽  
Assay Methods

Advances in protein-protein interaction (PPI) detection technology and computational analysis methods have produced numerous PPI networks, whose completeness appears to depend on the extent of data derived from different PPI assay methods and the complexity of the studied organism. Despite the partial nature of human PPI networks, computational data integration and analyses helped to elucidate new interactions and disease pathways. The success of computational analyses considerably depends on PPI data understanding. Exploration of the data and verification of their quality requires basic knowledge of the molecular biology of PPIs and familiarity with the assay methods used to detect PPIs. Both topics are reviewed in this chapter. After introducing various types of PPIs the principles of selected PPI assays are explained and their limitations discussed. Case studies of the Wnt signaling pathway and splice regulation demonstrate some of the challenges and opportunities that arise from assaying and analyzing PPIs. The chapter is concluded with an extrapolation to human systems biology that offers a glimpse into the future of PPI networks.

scholarly journals Selective Affimers Recognize BCL-2 Family Proteins Through Non-Canonical Structural Motifs

2019 ◽  
Author(s):  
Jennifer A. Miles ◽  
Fruzsina Hobor ◽  
James Taylor ◽  
Christian Tiede ◽  
Philip R. Rowell ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Cell Biology ◽  
Competitive Inhibition ◽  
Antibody Binding ◽  
Proof Of Concept ◽  
Protein Protein Interactions ◽  
The Family ◽  
Selective Ligands ◽  
Binding Cleft ◽  
Characterisation Methods

AbstractThe BCL-2 family is a challenging set of proteins to target selectively due to sequence and structural homologies across the family. Selective ligands for the BCL-2 family regulators of apoptosis are desirable as probes to understand cell biology and apoptotic signalling pathways, and as starting points for inhibitor design. We have used phage display to isolate Affimer reagents (non-antibody binding proteins based on a conserved scaffold) to identify ligands for MCL-1, BCL-xL, BCL-2, BAK and BAX, then used multiple biophysical characterisation methods to probe the interactions. We established that purified Affimers elicit selective and potent recognition of their target BCL-2 protein. For anti-apoptotic targets, competitive inhibition of their canonical protein-protein interactions is demonstrated. Co-crystal structures reveal an unprecedented mode of molecular recognition; where a BH3 helix is normally bound, flexible loops from the Affimer dock into the BH3 binding cleft. Moreover, the Affimers induce a change in the target proteins towards a desirable drug bound like conformation. These results indicate Affimers can be used as alternative templates to inspire design of selective BCL-2 family modulators, and provide proof-of-concept for the elaboration of selective non-antibody binding reagents for use in cell-biology applications.

S100 proteins and their influence on pro-survival pathways in cancer

2004 ◽  
Vol 82 (4) ◽  
pp. 508-515 ◽  
Author(s):  
Ethan D Emberley ◽  
Leigh C Murphy ◽  
Peter H Watson
Keyword(s):  
Cancer Progression ◽  
Protein Interactions ◽  
S100 Proteins ◽  
Amino Acid Residues ◽  
Protein Protein Interactions ◽  
Effector Molecules ◽  
Common Structure ◽  
Survival Pathways ◽  
Response Differentiation ◽  
Apoptosis Pathways

The S100 gene family is composed of at least 20 members that share a common structure defined in part by the Ca2+ binding EF-hand motif. These genes which are expressed in a discriminate fashion in specific cells and tissues, have been described to have either an intracellular or extracellular function, or both. S100 proteins are implicated in the immune response, differentiation, cytoskeleton dynamics, enzyme activity, Ca2+ homeostasis and growth. A potential role for S100 proteins in neoplasia stems from these activities and from the observation that several S100 proteins have altered levels of expression in different stages and types of cancer. While the precise role and importance of S100 proteins in the development and promotion of cancer is poorly understood, it appears that the binding of Ca2+ is essential for exposing amino acid residues that are important in forming protein-protein interactions with effector molecules. The identity of some of these effector molecules has also now begun to emerge, and with this the elucidation of the signaling pathways that are modulated by these proteins. Some of these interactions are consistent with the diverse functions noted above. Others suggest that, many S100s may also promote cancer progression through specific roles in cell survival and apoptosis pathways. This review summarizes these findings and their implications.

scholarly journals The Use of Peptides in the Treatment of Fragile X Syndrome: Challenges and Opportunities

2021 ◽  
Vol 12 ◽  
Author(s):  
Alice Romagnoli ◽  
Daniele Di Marino
Keyword(s):  
Fragile X Syndrome ◽  
Protein Interactions ◽  
Rna Binding ◽  
Fragile X ◽  
Pharmaceutical Research ◽  
Autism Spectrum ◽  
New Drugs ◽  
Protein Protein Interactions ◽  
Wide Range ◽  
Challenges And Opportunities

Fragile X Syndrome (FXS) is the most frequent cause of inherited intellectual disabilities and autism spectrum disorders, characterized by cognitive deficits and autistic behaviors. The silencing of the Fmr1 gene and consequent lack of FMRP protein, is the major contribution to FXS pathophysiology. FMRP is an RNA binding protein involved in the maturation and plasticity of synapses and its absence culminates in a range of morphological, synaptic and behavioral phenotypes. Currently, there are no approved medications for the treatment of FXS, with the approaches under study being fairly specific and unsatisfying in human trials. Here we propose peptides/peptidomimetics as candidates in the pharmacotherapy of FXS; in the last years this class of molecules has catalyzed the attention of pharmaceutical research, being highly selective and well-tolerated. Thanks to their ability to target protein-protein interactions (PPIs), they are already being tested for a wide range of diseases, including cancer, diabetes, inflammation, Alzheimer's disease, but this approach has never been applied to FXS. As FXS is at the forefront of efforts to develop new drugs and approaches, we discuss opportunities, challenges and potential issues of peptides/peptidomimetics in FXS drug design and development.

scholarly journals The interaction of verprolin WIRE with the adapter proteins family intersectin

2019 ◽  
Vol 17 (1) ◽  
pp. 3-7
Author(s):  
S. V. Kropyvko ◽  
A. V. Rynditch
Keyword(s):  
Actin Cytoskeleton ◽  
Protein Interactions ◽  
Adapter Proteins ◽  
Protein Protein Interactions ◽  
Sh3 Domains ◽  
Invasion And Migration ◽  
The Family ◽  
Cellular Signal ◽  
And Migration ◽  
Cytoskeleton Rearrangements

Aim. WIRE is a scafold protein that regulates actin cytoskeleton rearrangements and the formation of actin enriched membrane processes responsible for invasion and migration. ITSN1 and ITSN2 are representatives of the family of intersectins who participate in the reorganization of the actin cytoskeleton, as well as in other processes, such as endo/enzocytosis, cellular signal transduction, etc. As these proteins participate in the same processes, we checked their interaction with each other. Methods. Protein-protein interactions were identified using the GST pull-down method. Results. We showed that the SH3 domains of ITSN1 and ITSN2 interact with WIRE, and found that while WIRE is in a complex with endogenous actin. Conclusions. ITSN1 and ITSN2 interact with WIRE, which is located in a complex with endogenous actin. Keywords: WIRE, ITSN1 and ITSN2, actin.

scholarly journals Crystal Structure of PAV1-137: A Protein from the Virus PAV1 That InfectsPyrococcus abyssi

Archaea ◽  
2013 ◽  
Vol 2013 ◽  
pp. 1-5
Author(s):  
N. Leulliot ◽  
S. Quevillon-Cheruel ◽  
M. Graille ◽  
C. Geslin ◽  
D. Flament ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Focal Adhesion ◽  
Protein Interactions ◽  
Unknown Function ◽  
Structural Studies ◽  
Protein Protein Interactions ◽  
Helical Bundle ◽  
Putative Protein ◽  
The Family ◽  
Pyrococcus Abyssi

Pyrococcus abyssivirus 1 (PAV1) was the first virus particle infecting a hyperthermophilic Euryarchaeota (Pyrococcus abyssistrain GE23) that has been isolated and characterized. It is lemon shaped and is decorated with a short fibered tail. PAV1 morphologically resembles the fusiform members of the family Fuselloviridae or the genusSalterprovirus. The 18 kb dsDNA genome of PAV1 contains 25 predicted genes, most of them of unknown function. To help assigning functions to these proteins, we have initiated structural studies of the PAV1 proteome. We determined the crystal structure of a putative protein of 137 residues (PAV1-137) at a resolution of 2.2 Å. The protein forms dimers both in solution and in the crystal. The fold of PAV1-137 is a four-α-helical bundle analogous to those found in some eukaryotic adhesion proteins such as focal adhesion kinase, suggesting that PAV1-137 is involved in protein-protein interactions.

scholarly journals Analysis of protein–protein interactions in the feline calicivirus replication complex

2006 ◽  
Vol 87 (2) ◽  
pp. 363-368 ◽  
Author(s):  
William J. Kaiser ◽  
Yasmin Chaudhry ◽  
Stanislav V. Sosnovtsev ◽  
Ian G. Goodfellow
Keyword(s):  
Capsid Protein ◽  
Protein Interactions ◽  
Feline Calicivirus ◽  
Protein Protein Interactions ◽  
Replication Complex ◽  
Orf2 Protein ◽  
The Family ◽  
Capsid Protein Vp1 ◽  
The Individual

Caliciviruses are a major cause of gastroenteritis in humans and cause a wide variety of other diseases in animals. Here, the characterization of protein–protein interactions between the individual proteins of Feline calicivirus (FCV), a model system for other members of the family Caliciviridae, is reported. Using the yeast two-hybrid system combined with a number of other approaches, it is demonstrated that the p32 protein (the picornavirus 2B analogue) of FCV interacts with p39 (2C), p30 (3A) and p76 (3CD). The FCV protease/RNA polymerase (ProPol) p76 was found to form homo-oligomers, as well as to interact with VPg and ORF2, the region encoding the major capsid protein VP1. A weak interaction was also observed between p76 and the minor capsid protein encoded by ORF3 (VP2). ORF2 protein was found to interact with VPg, p76 and VP2. The potential roles of the interactions in calicivirus replication are discussed.

scholarly journals COMMD Proteins, a Novel Family of Structural and Functional Homologs of MURR1

2005 ◽  
Vol 280 (23) ◽  
pp. 22222-22232 ◽  
Author(s):  
Ezra Burstein ◽  
Jamie E. Hoberg ◽  
Amanda S. Wilkinson ◽  
Julie M. Rumble ◽  
Rebecca A. Csomos ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Nuclear Translocation ◽  
Nuclear Factor Κb ◽  
Protein Protein Interactions ◽  
Multifunctional Protein ◽  
New Family ◽  
The Family ◽  
Eukaryotic Organisms ◽  
Pleiotropic Functions ◽  
Cycle Regulation

MURR1 is a multifunctional protein that inhibits nuclear factor κB (NF-κB), a transcription factor with pleiotropic functions affecting innate and adaptive immunity, apoptosis, cell cycle regulation, and oncogenesis. Here we report the discovery of a new family of proteins with homology to MURR1. These proteins form multimeric complexes and were identified in a biochemical screen for MURR1-associated factors. The family is defined by the presence of a conserved and unique motif termed the COMM (copper metabolism gene MURR1) domain, which functions as an interface for protein-protein interactions. Like MURR1, several of these factors also associate with and inhibit NF-κB. The proteins designated as COMMD or COMM domain containing 1–10 are extensively conserved in multicellular eukaryotic organisms and define a novel family of structural and functional homologs of MURR1. The prototype of this family, MURR1/COMMD1, suppresses NF-κB not by affecting nuclear translocation or binding of NF-κB to cognate motifs; rather, it functions in the nucleus by affecting the association of NF-κB with chromatin.

scholarly journals Transmission distortion and genetic incompatibilities between alleles in a multigenerational mouse advanced intercross line

Genetics ◽  
2021 ◽  
Author(s):  
Danny Arends ◽  
Stefan Kärst ◽  
Sebastian Heise ◽  
Paula Korkuc ◽  
Deike Hesse ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Complex Traits ◽  
Inbred Strains ◽  
Parental Origin ◽  
Protein Protein Interactions ◽  
Sequencing Data ◽  
Synonymous Snps ◽  
Advanced Intercross Line ◽  
Apoptosis Pathways ◽  
Overrepresentation Analysis

Abstract While direct additive and dominance effects on complex traits have been mapped repeatedly, additional genetic factors contributing to the heterogeneity of complex traits have been scarcely investigated. To assess genetic background effects, we investigated transmission ratio distortions (TRDs) of alleles from parent to offspring using an advanced intercross line (AIL) of an initial cross between the mouse inbred strains C57BL/6NCrl (B6N) and BFMI860-12 (BFMI). 341 males of generation 28 and their respective 61 parents and 66 grandparents were genotyped using Mega Mouse Universal Genotyping Arrays (MegaMUGA). TRDs were investigated using allele transmission asymmetry tests, and pathway overrepresentation analysis was performed. Sequencing data was used to test for overrepresentation of non-synonymous SNPs in TRD regions. Genetic incompatibilities were tested using the Bateson-Dobzhansky-Muller two-locus model. 62 TRD regions were detected, many in close proximity to the telocentric centromere. TRD regions contained 44.5% more non-synonymous SNPs than randomly selected regions (182 vs. 125.9 ± 17.0, P < 1x10−4). Testing for genetic incompatibilities between TRD regions identified 29 genome-wide significant incompatibilities between TRD regions (P(BF) < 0.05). Pathway overrepresentation analysis of genes in TRD regions showed that DNA methylation, epigenetic regulation of RNA, and meiotic/meiosis regulation pathways were affected independent of the parental origin of the TRD. Paternal BFMI TRD regions showed overrepresentation in the small interfering RNA (siRNA) biogenesis and in the metabolism of lipids and lipoproteins. Maternal B6N TRD regions harbored genes involved in meiotic recombination, cell death, and apoptosis pathways. The analysis of genes in TRD regions suggests the potential distortion of protein-protein interactions influencing obesity and diabetic retinopathy as a result of disadvantageous combinations of allelic variants in Aass, Pgx6 and Nme8. Using an AIL significantly improves the resolution at which we can investigate TRD. Our analysis implicates distortion of protein-protein interactions as well as meiotic drive as the underlying mechanisms leading to the observed TRD in our AIL. Furthermore, genes with large amounts of non-synonymous SNPs located in TRD regions are more likely to be involved in pathways that are related to the phenotypic differences between the parental strains. Genes in these TRD regions provide new targets for investigating genetic adaptation, protein-protein interactions, and determinants of complex traits such as obesity.

scholarly journals Regulation of the phosphatase PP2B by protein–protein interactions

2016 ◽  
Vol 44 (5) ◽  
pp. 1313-1319 ◽  
Author(s):  
Patrick J. Nygren ◽  
John D. Scott
Keyword(s):  
Protein Interactions ◽  
Protein Phosphatase ◽  
Therapeutic Benefit ◽  
Protein Protein Interactions ◽  
Binding Motifs ◽  
Protein Substrates ◽  
Protein Phosphatase 2B ◽  
Anchoring Protein ◽  
Protein Dephosphorylation

Protein dephosphorylation is important for regulating cellular signaling in a variety of contexts. Protein phosphatase-2B (PP2B), or calcineurin, is a widely expressed serine/threonine phosphatase that acts on a large cross section of potential protein substrates when activated by increased levels of intracellular calcium in concert with calmodulin. PxIxIT and LxVP targeting motifs are important for maintaining specificity in response to elevated calcium. In the present study, we describe the mechanism of PP2B activation, discuss its targeting by conserved binding motifs and review recent advances in the understanding of an A-kinase anchoring protein 79/PP2B/protein kinase A complex's role in synaptic long-term depression. Finally, we discuss potential for targeting PP2B anchoring motifs for therapeutic benefit.

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