The four syndecans identified in mammals are membrane proteoglycans that play major roles in regulating cell behavior, cell signaling, and cell‐matrix interactions. The membrane forms of these ...syndecans function as receptors and co‐receptors. Their ectodomains, which are proteolytically released in the extracellular matrix by shedding, also regulate various biological processes. Apart from the cytoplasmic domain of syndecan‐4, the 3D structures of syndecans are poorly characterized, which hinders our understanding of the molecular mechanisms underlying syndecan functions that are mediated by numerous interactions. This mini‐review summarizes the structural data that are available for syndecans and provides a comprehensive syndecan interactome, which comprises three hundred and fifty‐one partners, including those identified by the high‐throughput method affinity purification‐mass spectrometry. It also gives a perspective on future studies of syndecan structures and interactions, which are required to further elucidate the molecular recognition processes that mediate the biological roles of the membrane and shed forms of syndecans.
The four mammalian syndecans are membrane proteoglycans involved in regulating cell behavior, cell signaling, and cell‐matrix interactions. 3D structures are available for their cytoplasmic and transmembrane domains but not for their ectodomains, which are enriched in intrinsic disorder. Their global interaction network comprises 351 proteins, whereas their consensus interactome contains 14 partners, which are mostly intracellular. In this review, we summarize the available structural data for syndecans and their interactome.
Numerous extracellular proteins and glycosaminoglycans (GAGs) undergo limited enzymatic cleavage resulting in the release of fragments exerting biological activities, which are usually different from ...those of the full‐length molecules. In this review, we define matrikines and matricryptins, which are bioactive fragments released from the extracellular matrix proteins, proteoglycans and GAGs and report their major biological activities. These fragments regulate a number of physiopathological processes including angiogenesis, cancer, fibrosis, inflammation, neurodegenerative diseases and wound healing. The challenges to translate these fragments from molecules biologically active in vitro and in experimental models to potential drugs are discussed in the last part of the review.
Extracellular matrix (ECM) is a dynamic 3‐dimensional network of macromolecules that provides structural support for the cells and tissues. Accumulated knowledge clearly demonstrated over the last ...decade that ECM plays key regulatory roles since it orchestrates cell signaling, functions, properties and morphology. Extracellularly secreted as well as cell‐bound factors are among the major members of the ECM family. Proteins/glycoproteins, such as collagens, elastin, laminins and tenascins, proteoglycans and glycosaminoglycans, hyaluronan, and their cell receptors such as CD44 and integrins, responsible for cell adhesion, comprise a well‐organized functional network with significant roles in health and disease. On the other hand, enzymes such as matrix metalloproteinases and specific glycosidases including heparanase and hyaluronidases contribute to matrix remodeling and affect human health. Several cell processes and functions, among them cell proliferation and survival, migration, differentiation, autophagy, angiogenesis, and immunity regulation are affected by certain matrix components. Structural alterations have been also well associated with disease progression. This guide on the composition and functions of the ECM gives a broad overview of the matrisome, the major ECM macromolecules, and their interaction networks within the ECM and with the cell surface, summarizes their main structural features and their roles in tissue organization and cell functions, and emphasizes the importance of specific ECM constituents in disease development and progression as well as the advances in molecular targeting of ECM to design new therapeutic strategies.
Extracellular matrices (ECMs) are well‐orchestrated 3D ultrastructures that supportively encompass cells. ECM macromolecules include collagens, proteoglycans/glycosaminoglycans, laminins, elastin, other proteins/glycoproteins, proteolytic, and glycolytic enzymes. Cell‐matrix interactions via cell surface receptors, such as integrins and CD44, mediate biochemical and biomechanical signals to adapt cellular functions. ECM remodeling is critical in health and disease. This guide condensates main ECM structural components and their ability to cross‐interact and regulate cellular behavior
The lysyl oxidase family comprises five members in mammals, lysyl oxidase (LOX) and four lysyl oxidase like proteins (LOXL1-4). They are copper amine oxidases with a highly conserved catalytic ...domain, a lysine tyrosylquinone cofactor, and a conserved copper-binding site. They catalyze the first step of the covalent cross-linking of the extracellular matrix (ECM) proteins collagens and elastin, which contribute to ECM stiffness and mechanical properties. The role of LOX and LOXL2 in fibrosis, tumorigenesis, and metastasis, including changes in their expression level and their regulation of cell signaling pathways, have been extensively reviewed, and both enzymes have been identified as therapeutic targets. We review here the molecular features and three-dimensional structure/models of LOX and LOXLs, their role in ECM cross-linking, and the regulation of their cross-linking activity by ECM proteins, proteoglycans, and by inhibitors. We also make an overview of the major ECM cross-links, because they are the ultimate molecular readouts of LOX/LOXL activity in tissues. The recent 3D model of LOX, which recapitulates its known structural and biochemical features, will be useful to decipher the molecular mechanisms of LOX interaction with its various substrates, and to design substrate-specific inhibitors, which are potential antifibrotic and antitumor drugs.
The six mammalian glycosaminoglycans (GAGs), chondroitin sulfate, dermatan sulfate, heparin, heparan sulfate, hyaluronan, and keratan sulfate, are linear polysaccharides. Except for hyaluronan, they ...are sulfated to various extent, and covalently attached to proteins to form proteoglycans. GAGs interact with growth factors, morphogens, chemokines, extracellular matrix proteins and their bioactive fragments, receptors, lipoproteins, and pathogens. These interactions mediate their functions, from embryonic development to extracellular matrix assembly and regulation of cell signaling in various physiological and pathological contexts such as angiogenesis, cancer, neurodegenerative diseases, and infections. We give an overview of GAG–protein interactions (i.e., specificity and chemical features of GAG- and protein-binding sequences), and review the available GAG–protein interaction networks. We also provide the first comprehensive draft of the GAG interactome composed of 832 biomolecules (827 proteins and five GAGs) and 932 protein–GAG interactions. This network is a scaffold, which in the future should integrate structures of GAG–protein complexes, quantitative data of the abundance of GAGs in tissues to build tissue-specific interactomes, and GAG interactions with metal ions such as calcium, which plays a major role in the assembly of the extracellular matrix and its interactions with cells. This contextualized interactome will be useful to identify druggable GAG–protein interactions for therapeutic purpose:
The collagen network is altered in fibrotic diseases associated with extracellular matrix (ECM) biosynthesis and remodeling. This mini-review focuses on the quantitative and qualitative modifications ...of collagens occurring at the molecular and tissue levels in fibrosis. They result from changes in collagen expression, biosynthesis, enzymatic cross-linking and degradation by several protease families. These molecular modifications, which are mostly regulated by TGF-β, are associated with altered collagen organization at the tissue level, leading to a fibrotic signature that can be analyzed by Second Harmonic Generation (SHG) microscopy.
•Expression of collagens in fibrosis is mostly driven by TGF-β, which cross-talks with other signaling pathways•Collagen deposition in fibrosis involves processing and degradation enzymes modulated by growth factors and cell receptors•Collagen covalent cross-linking mediated by lysyl oxidase and peroxidasin increases in fibrosis•Collagen signature in fibrotic tissues can be assessed by Second Harmonic Generation microscopy
Numerous extracellular proteins, growth factors, chemokines, cytokines, enzymes, lipoproteins, involved in a variety of biological processes, interact with heparin and/or heparan sulfate at the cell ...surface and in the extracellular matrix (ECM). The goal of this study is to investigate the relationship(s) between affinity and kinetics of heparin–protein interactions and the localization of the proteins, their intrinsic disorder and their biological roles. Most proteins bind to heparin with a higher affinity than their fragments and form more stable complexes with heparin than with heparan sulfate. Lipoproteins and matrisome-associated proteins (e.g. growth factors and cytokines) bind to heparin with very high affinity. Matrisome-associated proteins form transient complexes with heparin. However they bind to this glycosaminoglycan with a higher affinity than the proteins of the core matrisome, which contribute to ECM assembly and organization, and than the secreted proteins which are not associated with the ECM. The association rate of proteins with heparin is related to the intrinsic disorder of heparin-binding sites. Enzyme inhibitor activity, protein dimerization, skeletal system development and pathways in cancer are functionally associated with proteins displaying a high or very high affinity for heparin (KD<100nM). Besides their use in investigating molecular recognition and functions, kinetics and affinity are essential to prioritize interactions in networks and to build network models as discussed for the interaction network established at the surface of endothelial cells by endostatin, a heparin-binding protein regulating angiogenesis.
•Lipoproteins and matrisome-associated proteins bind heparin with very high affinity•Matrisome-associated proteins form transient complexes with heparin•The association rate increases with the disorder of heparin-binding sites•KEGG pathways in cancer are mediated by high affinity heparin–protein interactions•Kinetics and affinity are used to prioritize interactions and build network models
•A PFAS mixture was examined in association with cardiometabolic health in Nunavik.•PFAS were associated with increases in lipoproteins and prediabetes.•No associations were observed with diabetes ...and high blood pressure.
The cardiometabolic health status of Inuit in Nunavik has worsened in the last thirty years. The high concentrations of perfluoroalkyl acids (PFAAs) may be contributing to this since PFAAs have been linked with hypercholesterolemia, diabetes, and high blood pressure. The aim of this study was to examine the association between a PFAAs mixture and lipid profiles, Type II diabetes, prediabetes, and high blood pressure in this Inuit population.
We included 1212 participants of the Qanuilirpitaa? 2017 survey aged 16–80 years. Two mixture models (quantile g-computation and Bayesian Kernel Machine Regression (BKMR)) were used to investigate the associations between six PFAAs (PFHxS, PFOS, PFOA and three long-chain PFAAs (PFNA, PFDA and PFUnDA)) with five lipid profiles and three cardiometabolic outcomes. Non-linearity and interaction between PFAAs were further assessed.
An IQR increase in all PFAAs congeners resulted in an increase in total cholesterol (β 0.15, 95% confidence interval (CI) 0.06, 0.24), low-density lipoprotein cholesterol (LDL) (β 0.08, 95% CI 0.01, 0.16), high-density lipoprotein cholesterol (HDL) (β 0.04, 95% CI 0.002, 0.08), apolipoprotein B-100 (β 0.03, 95% CI 0.004, 0.05), and prediabetes (OR 1.80, 95% CI 1.11, 2.91). There was no association between PFAAs and triglycerides, diabetes, or high blood pressure. Long-chain PFAAs congeners were the main contributors driving the associations. Associations were largely linear, and there was no evidence of interaction between the PFAAs congeners.
Our study provides further evidence of increasing circulating lipids with increased exposure to PFAAs. The increased risk of prediabetes points to the influence of PFAAs on potential clinical outcomes. International regulation of PFAAs is essential to curb PFAAs exposure and related health effects in Arctic communities.
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