Copper transporters and copper chaperones: roles in cardiovascular physiology and disease

Copper (Cu) is an essential micronutrient but excess Cu is potentially toxic. Its important propensity to cycle between two oxidation states accounts for its frequent presence as a cofactor in many physiological processes through Cu-containing enzymes, including mitochondrial energy production (via cytochrome c-oxidase), protection against oxidative stress (via superoxide dismutase), and extracellular matrix stability (via lysyl oxidase). Since free Cu is potentially toxic, the bioavailability of intracellular Cu is tightly controlled by Cu transporters and Cu chaperones. Recent evidence reveals that these Cu transport systems play an essential role in the physiological responses of cardiovascular cells, including cell growth, migration, angiogenesis and wound repair. In response to growth factors, cytokines, and hypoxia, their expression, subcellular localization, and function are tightly regulated. Cu transport systems and their regulators have also been linked to various cardiovascular pathophysiologies such as hypertension, inflammation, atherosclerosis, diabetes, cardiac hypertrophy, and cardiomyopathy. A greater appreciation of the central importance of Cu transporters and Cu chaperones in cell signaling and gene expression in cardiovascular biology offers the possibility of identifying new therapeutic targets for cardiovascular disease.

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Matrix Metalloproteinases in Invertebrates

Protein and Peptide Letters ◽

10.2174/0929866527666200429110945 ◽

2020 ◽

Vol 27 (11) ◽

pp. 1068-1081

Author(s):

Xi Liu ◽

Dongwu Liu ◽

Yangyang Shen ◽

Mujie Huang ◽

Lili Gao ◽

...

Keyword(s):

Matrix Metalloproteinases ◽

Immune Responses ◽

Theoretical Basis ◽

Regulatory Mechanism ◽

Structure And Function ◽

Catalytic Domains ◽

Physiological Processes ◽

Disease Occurrence ◽

Complex Functions ◽

And Function

Matrix Metalloproteinases (MMPs) belong to a family of metal-dependent endopeptidases which contain a series of conserved pro-peptide domains and catalytic domains. MMPs have been widely found in plants, animals, and microorganisms. MMPs are involved in regulating numerous physiological processes, pathological processes, and immune responses. In addition, MMPs play a key role in disease occurrence, including tumors, cardiovascular diseases, and other diseases. Compared with invertebrate MMPs, vertebrate MMPs have diverse subtypes and complex functions. Therefore, it is difficult to study the function of MMPs in vertebrates. However, it is relatively easy to study invertebrate MMPs because there are fewer subtypes of MMPs in invertebrates. In the present review, the structure and function of MMPs in invertebrates were summarized, which will provide a theoretical basis for investigating the regulatory mechanism of MMPs in invertebrates.

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Genome-wide identification and analysis of class III peroxidases in Betula pendula

BMC Genomics ◽

10.1186/s12864-021-07622-1 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Kewei Cai ◽

Huixin Liu ◽

Song Chen ◽

Yi Liu ◽

Xiyang Zhao ◽

...

Keyword(s):

Stress Responses ◽

Betula Pendula ◽

Expression Patterns ◽

Class Iii ◽

Physiological Processes ◽

Plant Life ◽

Genome Wide ◽

Plant Life Cycle ◽

Class Iii Peroxidases ◽

And Function

Abstract Background Class III peroxidases (POD) proteins are widely present in the plant kingdom that are involved in a broad range of physiological processes including stress responses and lignin polymerization throughout the plant life cycle. At present, POD genes have been studied in Arabidopsis, rice, poplar, maize and Chinese pear, but there are no reports on the identification and function of POD gene family in Betula pendula. Results We identified 90 nonredundant POD genes in Betula pendula. (designated BpPODs). According to phylogenetic relationships, these POD genes were classified into 12 groups. The BpPODs are distributed in different numbers on the 14 chromosomes, and some BpPODs were located sequentially in tandem on chromosomes. In addition, we analyzed the conserved domains of BpPOD proteins and found that they contain highly conserved motifs. We also investigated their expression patterns in different tissues, the results showed that some BpPODs might play an important role in xylem, leaf, root and flower. Furthermore, under low temperature conditions, some BpPODs showed different expression patterns at different times. Conclusions The research on the structure and function of the POD genes in Betula pendula plays a very important role in understanding the growth and development process and the molecular mechanism of stress resistance. These results lay the theoretical foundation for the genetic improvement of Betula pendula.

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Dill Extract Induces Elastic Fiber Neosynthesis and Functional Improvement in the Ascending Aorta of Aged Mice with Reversal of Age-Dependent Cardiac Hypertrophy and Involvement of Lysyl Oxidase-Like-1

Biomolecules ◽

10.3390/biom10020173 ◽

2020 ◽

Vol 10 (2) ◽

pp. 173 ◽

Cited By ~ 2

Author(s):

Wassim Fhayli ◽

Quentin Boëté ◽

Nadjib Kihal ◽

Valérie Cenizo ◽

Pascal Sommer ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Lysyl Oxidase ◽

Elastic Fiber ◽

Ascending Aorta ◽

Functional Improvement ◽

Elastic Fibers ◽

Aged Mice ◽

Age Related ◽

And Function

Elastic fibers (90% elastin, 10% fibrillin-rich microfibrils) are synthesized only in early life and adolescence mainly by the vascular smooth muscle cells through the cross-linking of its soluble precursor, tropoelastin. Elastic fibers endow the large elastic arteries with resilience and elasticity. Normal vascular aging is associated with arterial remodeling and stiffening, especially due to the end of production and degradation of elastic fibers, leading to altered cardiovascular function. Several pharmacological treatments stimulate the production of elastin and elastic fibers. In particular, dill extract (DE) has been demonstrated to stimulate elastin production in vitro in dermal equivalent models and in skin fibroblasts to increase lysyl oxidase–like-1 (LOXL-1) gene expression, an enzyme contributing to tropoelastin crosslinking and elastin formation. Here, we have investigated the effects of a chronic treatment (three months) of aged male mice with DE (5% or 10% v/v, in drinking water) on the structure and function of the ascending aorta. DE treatment, especially at 10%, of aged mice protected pre-existing elastic lamellae, reactivated tropoelastin and LOXL-1 expressions, induced elastic fiber neo-synthesis, and decreased the stiffness of the aging aortic wall, probably explaining the reversal of the age-related cardiac hypertrophy also observed following the treatment. DE could thus be considered as an anti-aging product for the cardiovascular system.

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Proteolytic Events of Wound-Healing — Coordinated Interactions Among Matrix Metalloproteinases (MMPs), Integrins, and Extracellular Matrix Molecules

Critical Reviews in Oral Biology & Medicine ◽

10.1177/10454411010120050201 ◽

2001 ◽

Vol 12 (5) ◽

pp. 373-398 ◽

Cited By ~ 144

Author(s):

Bjorn Steffensen ◽

Lari Häkkinen ◽

Hannu Larjava

Keyword(s):

Extracellular Matrix ◽

Wound Healing ◽

Matrix Metalloproteinases ◽

Wound Repair ◽

Enzyme Activation ◽

Processing Enzymes ◽

The Matrix ◽

Signaling Receptors ◽

State Of Rest ◽

And Function

During wound-healing, cells are required to migrate rapidly into the wound site via a proteolytically generated pathway in the provisional matrix, to produce new extracellular matrix, and, subsequently, to remodel the newly formed tissue matrix during the maturation phase. Two classes of molecules cooperate closely to achieve this goal, namely, the matrix adhesion and signaling receptors, the integrins, and matrix-degrading and -processing enzymes, the matrix metalloproteinases (MMPs). There is now substantial experimental evidence that blocking key molecules of either group will prevent or seriously delay wound-healing. It has been known for some time now that cell adhesion by means of the integrins regulates the expression of MMPs. In addition, certain MMPs can bind to integrins or other receptors on the cell surface involved in enzyme activation, thereby providing a mechanism for localized matrix degradation. By proteolytically modifying the existing matrix molecules, the MMPs can then induce changes in cell behavior and function from a state of rest to migration. During wound repair, the expression of integrins and MMPs is simultaneously up-regulated. This review will focus on those aspects of the extensive knowledge of fibroblast and keratinocyte MMPs and integrins in biological processes that relate to wound-healing.

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Neuroprotective Function of 14-3-3 Proteins in Neurodegeneration

BioMed Research International ◽

10.1155/2013/564534 ◽

2013 ◽

Vol 2013 ◽

pp. 1-11 ◽

Cited By ~ 45

Author(s):

Tadayuki Shimada ◽

Alyson E. Fournier ◽

Kanato Yamagata

Keyword(s):

Neurodegenerative Disease ◽

Cellular Localization ◽

Experimental Studies ◽

Adaptor Proteins ◽

Vast Number ◽

Physiological Processes ◽

Binding Partners ◽

Neuroprotective Function ◽

And Function ◽

Regulation Of Enzyme Activity

14-3-3 proteins are abundantly expressed adaptor proteins that interact with a vast number of binding partners to regulate their cellular localization and function. They regulate substrate function in a number of ways including protection from dephosphorylation, regulation of enzyme activity, formation of ternary complexes and sequestration. The diversity of 14-3-3 interacting partners thus enables 14-3-3 proteins to impact a wide variety of cellular and physiological processes. 14-3-3 proteins are broadly expressed in the brain, and clinical and experimental studies have implicated 14-3-3 proteins in neurodegenerative disease. A recurring theme is that 14-3-3 proteins play important roles in pathogenesis through regulating the subcellular localization of target proteins. Here, we review the evidence that 14-3-3 proteins regulate aspects of neurodegenerative disease with a focus on their protective roles against neurodegeneration.

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Identification and functional characterization of the Piezo1 channel pore domain

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.015905 ◽

2020 ◽

pp. jbc.RA120.015905

Author(s):

Elena D Nosyreva ◽

David Thompson ◽

Ruhma Syeda

Keyword(s):

Functional Characterization ◽

Functional Study ◽

Heat Sensation ◽

Physiological Processes ◽

Structural Details ◽

Functional Understanding ◽

And Function ◽

Downstream Processes ◽

Pore Domain ◽

First Time

Mechanotransduction is the process by which cells convert physical forces into electro-chemical responses. On a molecular scale these forces are detected by mechanically activated ion channels, which constitute the basis for hearing, touch, pain, cold and heat sensation amongst other physiological processes. Exciting high-resolution structural details of these channels are currently emerging that will eventually allow us to delineate the molecular determinants of gating and ion permeation. However, our structural-functional understanding across the family remains limited. Piezo1 is one of the largest and least understood of these channels, with various structurally identified features within its trimeric assembly. This study seeks to determine the modularity and function of Piezo1 channels by constructing deletion proteins guided by cryo EM structural knowledge. Our comprehensive functional study identified, for the first time, the minimal amino acid sequence of the full-length Piezo1 that can fold and function as the channel’s pore domain between E2172 and the last residue E2547. While, the addition of an anchor region has no effect on permeation properties. The Piezo1 pore domain is not pressure sensitive and the appending of Piezo Repeat-A did not restore pressure-dependent gating, hence the sensing module must exist between residues 1-1952. Our efforts delineating the permeation and gating regions within this complex ion channel have implications in identifying small molecules that exclusively regulate the activity of the channel’s pore module to influence mechanotransduction and downstream processes.

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Intrinsically disordered proteins identified in the aggregate proteome serve as biomarkers of neurodegeneration

Metabolic Brain Disease ◽

10.1007/s11011-021-00791-8 ◽

2021 ◽

Author(s):

Srinivas Ayyadevara ◽

Akshatha Ganne ◽

Meenakshisundaram Balasubramaniam ◽

Robert J. Shmookler Reis

Keyword(s):

Intrinsically Disordered Proteins ◽

Protein Complexes ◽

Disordered Proteins ◽

Intrinsically Disordered ◽

Intrinsically Disordered Regions ◽

Physiological Processes ◽

Protein Partners ◽

And Function ◽

Computational Analyses ◽

Disordered Regions

AbstractA protein’s structure is determined by its amino acid sequence and post-translational modifications, and provides the basis for its physiological functions. Across all organisms, roughly a third of the proteome comprises proteins that contain highly unstructured or intrinsically disordered regions. Proteins comprising or containing extensive unstructured regions are referred to as intrinsically disordered proteins (IDPs). IDPs are believed to participate in complex physiological processes through refolding of IDP regions, dependent on their binding to a diverse array of potential protein partners. They thus play critical roles in the assembly and function of protein complexes. Recent advances in experimental and computational analyses predicted multiple interacting partners for the disordered regions of proteins, implying critical roles in signal transduction and regulation of biological processes. Numerous disordered proteins are sequestered into aggregates in neurodegenerative diseases such as Alzheimer’s disease (AD) where they are enriched even in serum, making them good candidates for serum biomarkers to enable early detection of AD.

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Role of co-regulators in metabolic and transcriptional actions of thyroid hormone

Journal of Molecular Endocrinology ◽

10.1530/jme-15-0246 ◽

2016 ◽

Vol 56 (3) ◽

pp. R73-R97 ◽

Cited By ~ 18

Author(s):

Inna Astapova

Keyword(s):

Thyroid Hormone ◽

Transcriptional Repression ◽

Target Genes ◽

Thyroid Hormone Receptor ◽

Retinoic Acid Receptor ◽

Specific Response ◽

Physiological Processes ◽

Genome Wide ◽

Wide Range ◽

And Function

Thyroid hormone (TH) controls a wide range of physiological processes through TH receptor (TR) isoforms. Classically, TRs are proposed to function as tri-iodothyronine (T3)-dependent transcription factors: on positively regulated target genes, unliganded TRs mediate transcriptional repression through recruitment of co-repressor complexes, while T3binding leads to dismissal of co-repressors and recruitment of co-activators to activate transcription. Co-repressors and co-activators were proposed to play opposite roles in the regulation of negative T3target genes and hypothalamic–pituitary–thyroid axis, but exact mechanisms of the negative regulation by TH have remained elusive. Important insights into the roles of co-repressors and co-activators in different physiological processes have been obtained using animal models with disrupted co-regulator function. At the same time, recent studies interrogating genome-wide TR binding have generated compelling new data regarding effects of T3, local chromatin structure, and specific response element configuration on TR recruitment and function leading to the proposal of new models of transcriptional regulation by TRs. This review discusses data obtained in various mouse models with manipulated function of nuclear receptor co-repressor (NCoR or NCOR1) and silencing mediator of retinoic acid receptor and thyroid hormone receptor (SMRT or NCOR2), and family of steroid receptor co-activators (SRCs also known as NCOAs) in the context of TH action, as well as insights into the function of co-regulators that may emerge from the genome-wide TR recruitment analysis.

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