Structure and properties of the Ca2+-binding CUB domain, a widespread ligand-recognition unit involved in major biological functions

2011 ◽  
Vol 439 (2) ◽  
pp. 185-193 ◽  
Author(s):  
Christine Gaboriaud ◽  
Lynn Gregory-Pauron ◽  
Florence Teillet ◽  
Nicole M. Thielens ◽  
Isabelle Bally ◽  
...  
Keyword(s):  
Binding Site ◽  
Protein Interactions ◽  
Current Knowledge ◽  
Density Lipoprotein ◽  
Extracellular Proteins ◽  
Present Review ◽  
Biological Functions ◽  
Protein Motifs ◽  
Wide Range ◽  
Cub Domain

CUB domains are 110-residue protein motifs exhibiting a β-sandwich fold and mediating protein–protein interactions in various extracellular proteins. Recent X-ray structural and mutagenesis studies have led to the identification of a particular CUB domain subset, cbCUB (Ca2+-binding CUB domain). Unlike other CUB domains, these harbour a homologous Ca2+-binding site that underlies a conserved binding site mediating ionic interaction between two of the three conserved acidic Ca2+ ligands and a basic (lysine or arginine) residue of a protein ligand, similar to the interactions mediated by the low-density lipoprotein receptor family. cbCUB-mediated protein–ligand interactions usually involve multipoint attachment through several cbCUBs, resulting in high-affinity binding through avidity, despite the low affinity of individual interactions. The aim of the present review is to summarize our current knowledge about the structure and functions of cbCUBs, which represent the majority of the known CUB repertoire and are involved in a variety of major biological functions, including immunity and development, as well as in various cancer types. Examples discussed in the present review include a wide range of soluble and membrane-associated human proteins, as well as some archaeal and invertebrate proteins. The fact that these otherwise unrelated proteins share a common Ca2+-dependent ligand-binding ability suggests a mechanism inheri-ted from very primitive ancestors. The information provided in the present review should stimulate further investigations on the crucial interactions mediated by cbCUB-containing proteins.

scholarly journals Sigmar1’s Molecular, Cellular, and Biological Functions in Regulating Cellular Pathophysiology

2021 ◽  
Vol 12 ◽  
Author(s):  
Richa Aishwarya ◽  
Chowdhury S. Abdullah ◽  
Mahboob Morshed ◽  
Naznin Sultana Remex ◽  
Md. Shenuarin Bhuiyan
Keyword(s):  
Protein Quality ◽  
Current Knowledge ◽  
Neuromuscular Disorder ◽  
Recessive Mutation ◽  
Biological Functions ◽  
Causative Gene ◽  
Sigma 1 Receptor ◽  
Ion Channel Regulation ◽  
Cellular Survival ◽  
Wide Range

The Sigma 1 receptor (Sigmar1) is a ubiquitously expressed multifunctional inter-organelle signaling chaperone protein playing a diverse role in cellular survival. Recessive mutation in Sigmar1 have been identified as a causative gene for neuronal and neuromuscular disorder. Since the discovery over 40 years ago, Sigmar1 has been shown to contribute to numerous cellular functions, including ion channel regulation, protein quality control, endoplasmic reticulum-mitochondrial communication, lipid metabolism, mitochondrial function, autophagy activation, and involved in cellular survival. Alterations in Sigmar1’s subcellular localization, expression, and signaling has been implicated in the progression of a wide range of diseases, such as neurodegenerative diseases, ischemic brain injury, cardiovascular diseases, diabetic retinopathy, cancer, and drug addiction. The goal of this review is to summarize the current knowledge of Sigmar1 biology focusing the recent discoveries on Sigmar1’s molecular, cellular, pathophysiological, and biological functions.

scholarly journals Genome Wide Analysis of Nucleotide-Binding Site Disease Resistance Genes inBrachypodium distachyon

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Shenglong Tan ◽  
Song Wu
Keyword(s):  
Disease Resistance ◽  
Binding Site ◽  
Resistance Genes ◽  
Brachypodium Distachyon ◽  
Nucleotide Binding ◽  
Nucleotide Binding Site ◽  
Disease Resistance Genes ◽  
Protein Motifs ◽  
Wide Range ◽  
Encoding Genes

Nucleotide-binding site (NBS) disease resistance genes play an important role in defending plants from a variety of pathogens and insect pests. Many R-genes have been identified in various plant species. However, little is known about the NBS-encoding genes inBrachypodium distachyon. In this study, using computational analysis of theB. distachyongenome, we identified 126 regular NBS-encoding genes and characterized them on the bases of structural diversity, conserved protein motifs, chromosomal locations, gene duplications, promoter region, and phylogenetic relationships. EST hits and full-length cDNA sequences (fromBrachypodiumdatabase) of 126 R-like candidates supported their existence. Based on the occurrence of conserved protein motifs such as coiled-coil (CC), NBS, leucine-rich repeat (LRR), these regular NBS-LRR genes were classified into four subgroups: CC-NBS-LRR, NBS-LRR, CC-NBS, and X-NBS. Further expression analysis of the regular NBS-encoding genes inBrachypodiumdatabase revealed that these genes are expressed in a wide range of libraries, including those constructed from various developmental stages, tissue types, and drought challenged or nonchallenged tissue.

Evolutionary selection for protein aggregation

2012 ◽  
Vol 40 (5) ◽  
pp. 1032-1037 ◽  
Author(s):  
Natalia Sanchez de Groot ◽  
Marc Torrent ◽  
Anna Villar-Piqué ◽  
Benjamin Lang ◽  
Salvador Ventura ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Protein Interactions ◽  
Current Knowledge ◽  
Protein Aggregates ◽  
Cellular Systems ◽  
Aggregation Process ◽  
Loss Of Function ◽  
Protein Protein Interactions ◽  
Wide Range ◽  
Range Of Functions

Protein aggregation is being found to be associated with an increasing number of human diseases. Aggregation can lead to a loss of function (lack of active protein) or to a toxic gain of function (cytotoxicity associated with protein aggregates). Although potentially harmful, protein sequences predisposed to aggregation seem to be ubiquitous in all kingdoms of life, which suggests an evolutionary advantage to having such segments in polypeptide sequences. In fact, aggregation-prone segments are essential for protein folding and for mediating certain protein–protein interactions. Moreover, cells use protein aggregates for a wide range of functions. Against this background, life has adapted to tolerate the presence of potentially dangerous aggregation-prone sequences by constraining and counteracting the aggregation process. In the present review, we summarize the current knowledge of the advantages associated with aggregation-prone stretches in proteomes and the strategies that cellular systems have developed to control the aggregation process.

scholarly journals Protein-Related Circular RNAs in Human Pathologies

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1841 ◽  
Author(s):  
Olga Wawrzyniak ◽  
Żaneta Zarębska ◽  
Konrad Kuczyński ◽  
Anna Gotz-Więckowska ◽  
Katarzyna Rolle
Keyword(s):  
Protein Interactions ◽  
Rna Binding ◽  
Current Knowledge ◽  
Close Association ◽  
Development Stage ◽  
Circular Rnas ◽  
Biological Functions ◽  
Bodily Fluids ◽  
Specific Manner ◽  
Regulate Protein

Circular RNAs (circRNAs) are a distinct family of RNAs derived from alternative splicing which play a crucial role in regulating gene expression by acting as microRNA (miRNA) and RNA binding protein (RBP) sponges. However, recent studies have also reported the multifunctional potential of these particles. Under different conditions, circRNAs not only regulate protein synthesis, destination, and degradation but can serve as protein scaffolds or recruiters and are also able to produce short peptides with active biological functions. circRNAs are under ongoing investigation because of their close association with the development of diseases. Some circRNAs are reportedly expressed in a tissue- and development stage-specific manner. Furthermore, due to other features of circRNAs, including their stability, conservation, and high abundance in bodily fluids, they are believed to be potential biomarkers for various diseases, including cancers. In this review, we focus on providing a summary of the current knowledge on circRNA–protein interactions. We present the properties and functions of circRNAs, the possible mechanisms of their translation abilities, and the emerging functions of circRNA-derived peptides in human pathologies.

scholarly journals p21-Activated Kinases in Thyroid Cancer

Endocrinology ◽  
2020 ◽  
Vol 161 (8) ◽  
Author(s):  
Luis Bautista ◽  
Christina M Knippler ◽  
Matthew D Ringel
Keyword(s):  
Breast Cancer ◽  
Thyroid Cancer ◽  
Cell Motility ◽  
Current Knowledge ◽  
Biological Functions ◽  
Cellular Functions ◽  
Cytoskeletal Rearrangement ◽  
Group I ◽  
Wide Range ◽  
The Family

Abstract The family of p21-activated kinases (PAKs) are oncogenic proteins that regulate critical cellular functions. PAKs play central signaling roles in the integrin/CDC42/Rho, ERK/MAPK, PI3K/AKT, NF-κB, and Wnt/β-catenin pathways, functioning both as kinases and scaffolds to regulate cell motility, mitosis and proliferation, cytoskeletal rearrangement, and other cellular activities. PAKs have been implicated in both the development and progression of a wide range of cancers, including breast cancer, pancreatic melanoma, thyroid cancer, and others. Here we will discuss the current knowledge on the structure and biological functions of both group I and group II PAKs, as well as the roles that PAKs play in oncogenesis and progression, with a focus on thyroid cancer and emerging data regarding BRAF/PAK signaling.

TB domain proteins: evolutionary insights into the multifaceted roles of fibrillins and LTBPs

2010 ◽  
Vol 433 (2) ◽  
pp. 263-276 ◽  
Author(s):  
Ian Robertson ◽  
Sacha Jensen ◽  
Penny Handford
Keyword(s):  
Extracellular Matrix ◽  
Growth Factor ◽  
Protein Interactions ◽  
Transforming Growth Factor ◽  
Covalent Binding ◽  
Extracellular Proteins ◽  
Sequence Information ◽  
Valuable Insight ◽  
Domain Organization ◽  
Wide Range

Fibrillins and LTBPs [latent TGFβ (transforming growth factor β)-binding proteins] perform vital and complex roles in the extracellular matrix and are relevant to a wide range of human diseases. These proteins share a signature ‘eight cysteine’ or ‘TB (TGFβ-binding protein-like)’ domain that is found nowhere else in the human proteome, and which has been shown to mediate a variety of protein–protein interactions. These include covalent binding of the TGFβ propeptide, and RGD-directed interactions with a repertoire of integrins. TB domains are found interspersed with long arrays of EGF (epidermal growth factor)-like domains, which occur more widely in extracellular proteins, and also mediate binding to a large number of proteins and proteoglycans. In the present paper, newly available protein sequence information from a variety of sources is reviewed and related to published findings on the structure and function of fibrillins and LTBPs. These sequences give valuable insight into the evolution of TB domain proteins and suggest that the fibrillin domain organization emerged first, over 600 million years ago, prior to the divergence of Cnidaria and Bilateria, after which it has remained remarkably unchanged. Comparison of sequence features and domain organization in such a diverse group of organisms also provides important insights into how fibrillins and LTBPs might perform their roles in the extracellular matrix.

scholarly journals Biological Functionalities of Transglutaminase 2 and the Possibility of Its Compensation by Other Members of the Transglutaminase Family

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Benedict Onyekachi Odii ◽  
Peter Coussons
Keyword(s):  
Substrate Specificity ◽  
Posttranslational Modification ◽  
Transglutaminase 2 ◽  
Extracellular Proteins ◽  
Gene Products ◽  
Biological Functions ◽  
Matrix Stabilization ◽  
Wide Range ◽  
Cell Growth And Differentiation ◽  
Cellular Development

Transglutaminase 2 (TG2) is the most widely distributed and most abundantly expressed member of the transglutaminase family of enzymes, a group of intracellular and extracellular proteins that catalyze the Ca2+-dependent posttranslational modification of proteins. It is a unique member of the transglutaminase family owing to its specialized biochemical, structural and functional elements, ubiquitous tissue distribution and subcellular localization, and substrate specificity. The broad substrate specificity of TG2 and its flexible interaction with numerous other gene products may account for its multiple biological functions. In addition to the classic Ca2+-dependent transamidation of proteins, which is a hallmark of transglutaminase enzymes, additional Ca2+-independent enzymatic and nonenzymatic activities of TG2 have been identified. Many such activities have been directly or indirectly implicated in diverse cellular physiological events, including cell growth and differentiation, cell adhesion and morphology, extracellular matrix stabilization, wound healing, cellular development, receptor-mediated endocytosis, apoptosis, and disease pathology. Given the wide range of activities of the transglutaminase gene family it has been suggested that, in the absence of active versions of TG2, its function could be compensated for by other members of the transglutaminase family. It is in the light of this assertion that we review, herein, TG2 activities and the possibilities and premises for compensation for its absence.

scholarly journals Ankyrin repeats in context with human population variation

2021 ◽  
Author(s):  
Javier S Utges ◽  
Maxim I Tsenkov ◽  
Noah JM Dietrich ◽  
Stuart A MacGowan ◽  
Geoffrey J Barton
Keyword(s):  
Protein Interactions ◽  
Human Population ◽  
Large Scale ◽  
Population Variation ◽  
Evolutionary Constraint ◽  
Ankyrin Repeats ◽  
Protein Protein Interactions ◽  
Protein Motifs ◽  
Missense Variants ◽  
Wide Range

Ankyrin protein repeats bind to a wide range of substrates and are one of the most common protein motifs in nature. Here, we collate a high-quality alignment of 7,407 ankyrin repeats and examine for the first time, the distribution of human population variants from large-scale sequencing of healthy individuals across this family. Population variants are not randomly distributed across the genome but are constrained by gene essentiality and function. Accordingly, we interpret the population variants in context with evolutionary constraint and structural features including secondary structure, accessibility and protein-protein interactions across 383 three-dimensional structures of ankyrin repeats. We find five positions that are highly conserved across homologs and also depleted in missense variants within the human population. These positions are significantly enriched in intra-domain contacts and so likely to be key for repeat packing. In contrast, a group of evolutionarily divergent positions are found to be depleted in missense variants in human but significantly enriched in protein-protein interactions. Our analysis also suggests the domain has three, not two surfaces, each with different patterns of enrichment in protein-substrate interactions and missense variants. Our findings will be of interest to those studying or engineering ankyrin-repeat containing proteins as well as those interpreting the significance of disease variants.

scholarly journals Ankyrin repeats in context with human population variation

2021 ◽  
Vol 17 (8) ◽  
pp. e1009335
Author(s):  
Javier S. Utgés ◽  
Maxim I. Tsenkov ◽  
Noah J. M. Dietrich ◽  
Stuart A. MacGowan ◽  
Geoffrey J. Barton
Keyword(s):  
Protein Interactions ◽  
Human Population ◽  
Large Scale ◽  
Population Variation ◽  
Evolutionary Constraint ◽  
Ankyrin Repeats ◽  
Protein Protein Interactions ◽  
Protein Motifs ◽  
Missense Variants ◽  
Wide Range

Ankyrin protein repeats bind to a wide range of substrates and are one of the most common protein motifs in nature. Here, we collate a high-quality alignment of 7,407 ankyrin repeats and examine for the first time, the distribution of human population variants from large-scale sequencing of healthy individuals across this family. Population variants are not randomly distributed across the genome but are constrained by gene essentiality and function. Accordingly, we interpret the population variants in context with evolutionary constraint and structural features including secondary structure, accessibility and protein-protein interactions across 383 three-dimensional structures of ankyrin repeats. We find five positions that are highly conserved across homologues and also depleted in missense variants within the human population. These positions are significantly enriched in intra-domain contacts and so likely to be key for repeat packing. In contrast, a group of evolutionarily divergent positions are found to be depleted in missense variants in human but significantly enriched in protein-protein interactions. Our analysis also suggests the domain has three, not two surfaces, each with different patterns of enrichment in protein-substrate interactions and missense variants. Our findings will be of interest to those studying or engineering ankyrin-repeat containing proteins as well as those interpreting the significance of disease variants.

Understanding the Molecular Basis of Cardiomyopathy

2021 ◽  
Author(s):  
Marie-Louise Bang ◽  
Julijus Bogomolovas ◽  
Ju Chen
Keyword(s):  
Molecular Basis ◽  
Current Knowledge ◽  
Present Review ◽  
American Physiological Society ◽  
Mortality And Morbidity ◽  
Specific Focus ◽  
Wide Range ◽  
Associated Proteins ◽  
Inherited Cardiomyopathies ◽  
Cellular Compartments

Inherited cardiomyopathies are a major cause of mortality and morbidity worldwide and can be caused by mutations in a wide range of proteins located in different cellular compartments. The present review is based on Dr. Ju Chen's 2021 Robert M. Berne Distinguished Lectureship of the American Physiological Society Cardiovascular section, in which he provided an overview of the current knowledge on the cardiomyopathy-associated proteins that have been studied in his laboratory. The review provides a general summary of the proteins in different compartments of cardiomyocytes associated with cardiomyopathies with specific focus on the proteins that have been studied in Dr. Chen's laboratory.

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