The physiology, pathology and potential therapeutic application of serotonylation

ABSTRACT The classical neurotransmitter serotonin or 5-hydroxytryptamine (5-HT), synthesized from tryptophan, can be produced both centrally and peripherally. Through binding to functionally distinct receptors, serotonin is profoundly implicated in a number of fundamental physiological processes and pathogenic conditions. Recently, serotonin has been found covalently incorporated into proteins, a newly identified post-translational modification termed serotonylation. Transglutaminases (TGMs), especially TGM2, are responsible for catalyzing the transamidation reaction by transferring serotonin to the glutamine residues of target proteins. Small GTPases, extracellular matrix protein fibronectin, cytoskeletal proteins and histones are the most reported substrates for serotonylation, and their functions are triggered by this post-translational modification. This Review highlights the roles of serotonylation in physiology and diseases and provides perspectives for pharmacological interventions to ameliorate serotonylation for disease treatment.

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β1 integrins are distributed in adhesion structures with fibronectin and caveolin and in coated pits

Biochemistry and Cell Biology ◽

10.1139/o03-063 ◽

2003 ◽

Vol 81 (5) ◽

pp. 335-348 ◽

Cited By ~ 9

Author(s):

Nikhat D Boyd ◽

Bosco M. C Chan ◽

Nils O Petersen

Keyword(s):

Extracellular Matrix ◽

Protein Kinase ◽

Matrix Protein ◽

Adaptor Protein ◽

Cytoskeletal Proteins ◽

Matrix Proteins ◽

Mitogen Activated Protein Kinase ◽

Extracellular Matrix Protein ◽

Coated Pits ◽

Mitogen Activated Protein

Integrins are found in adhesion structures, which link the extracelullar matrix to cytoskeletal proteins. Here, we attempt to further define the distribution of β1 integrins in the context of their association with matrix proteins and other cell surface molecules relevant to the endocytic process. We find that β1 integrins colocalize with fibronectin in fibrillar adhesion structures. A fraction of caveolin is also organized along these adhesion structures. The extracellular matrix protein laminin is not concentrated in these structures. The α4β1 integrin exhibits a distinct distribution from other β1 integrins after cells have adhered for 1 h to extracellular matrix proteins but is localized in adhesion structures after 24 h of adhesion. There are differences between the fibronectin receptors: α5β1 integrins colocalize with adaptor protein-2 in coated pits, while α4β1 integrins do not. This parallels our earlier observation that of the two laminin receptors, α1β1 and α6β1, only αaβ1 integrins colocalize with adaptor protein-2 in coated pits. Calcium chelation or inhibition of mitogen-activated protein kinase kinase, protein kinase C, or src did not affect localization of α1β1 and α5β1 integrins in coated pits. Likewise, the integrity of coated-pit structures or adhesion structures is not required for integrin and adaptor protein-2 colocalization. This suggests a robust and possibly constitutive interaction between these integrins and coated pits.Key words: adhesion, endocytosis, extracellular matrix, microscopy, confocal, signalling.

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1280: Increased Susceptibility to Genitovaginal Prolapse Associated with a Polymorphism in the Promoter of the Extracellular Matrix Protein LAMC1

The Journal of Urology ◽

10.1016/s0022-5347(18)31494-0 ◽

2007 ◽

Vol 177 (4S) ◽

pp. 421-422

Author(s):

Ganka Nikolova ◽

Christian O. Twiss ◽

Hane Lee ◽

Nelson Stanley ◽

Janet Sinsheimer ◽

...

Keyword(s):

Extracellular Matrix ◽

Matrix Protein ◽

Extracellular Matrix Protein ◽

Increased Susceptibility

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Homogenous overexpression of the extracellular matrix protein Netrin-1 in a hollow fiber bioreactor

Applied Microbiology and Biotechnology ◽

10.1007/s00253-021-11438-0 ◽

2021 ◽

Author(s):

Aniel Moya-Torres ◽

Monika Gupta ◽

Fabian Heide ◽

Natalie Krahn ◽

Scott Legare ◽

...

Keyword(s):

Extracellular Matrix ◽

Hollow Fiber ◽

Mammalian Cells ◽

Matrix Protein ◽

Continuous Production ◽

Extracellular Matrix Protein ◽

Close Monitoring ◽

High Quality ◽

Biolayer Interferometry ◽

Hollow Fiber Bioreactor

Abstract The production of recombinant proteins for functional and biophysical studies, especially in the field of structural determination, still represents a challenge as high quality and quantities are needed to adequately perform experiments. This is in part solved by optimizing protein constructs and expression conditions to maximize the yields in regular flask expression systems. Still, work flow and effort can be substantial with no guarantee to obtain improvements. This study presents a combination of workflows that can be used to dramatically increase protein production and improve processing results, specifically for the extracellular matrix protein Netrin-1. This proteoglycan is an axon guidance cue which interacts with various receptors to initiate downstream signaling cascades affecting cell differentiation, proliferation, metabolism, and survival. We were able to produce large glycoprotein quantities in mammalian cells, which were engineered for protein overexpression and secretion into the media using the controlled environment provided by a hollow fiber bioreactor. Close monitoring of the internal bioreactor conditions allowed for stable production over an extended period of time. In addition to this, Netrin-1 concentrations were monitored in expression media through biolayer interferometry which allowed us to increase Netrin-1 media concentrations tenfold over our current flask systems while preserving excellent protein quality and in solution behavior. Our particular combination of genetic engineering, cell culture system, protein purification, and biophysical characterization permitted us to establish an efficient and continuous production of high-quality protein suitable for structural biology studies that can be translated to various biological systems. Key points • Hollow fiber bioreactor produces substantial yields of homogenous Netrin-1 • Biolayer interferometry allows target protein quantitation in expression media • High production yields in the bioreactor do not impair Netrin-1 proteoglycan quality Graphical abstract

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AZP2006, a new promising treatment for Alzheimer’s and related diseases

Scientific Reports ◽

10.1038/s41598-021-94708-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

N. Callizot ◽

C. Estrella ◽

S. Burlet ◽

A. Henriques ◽

C. Brantis ◽

...

Keyword(s):

Therapeutic Application ◽

Neuroprotective Effects ◽

Beneficial Effects ◽

Potential Therapeutic Application ◽

Promising Treatment ◽

Central Synapses ◽

First Time ◽

Pgrn Level

AbstractProgranulin (PGRN) is a protein with multiple functions including the regulation of neuroinflammation, neuronal survival, neurite and synapsis growth. Although the mechanisms of action of PGRN are currently unknown, its potential therapeutic application in treating neurodegenerative diseases is huge. Thus, strategies to increase PGRN levels in patients could provide an effective treatment. In the present study, we investigated the effects of AZP2006, a lysotropic molecule now in phase 2a clinical trial in Progressive Supranuclear Palsy patients, for its ability to increase PGRN level and promote neuroprotection. We showed for the first time the in vitro and in vivo neuroprotective effects of AZP2006 in neurons injured with Aβ1–42 and in two different pathological animal models of Alzheimer’s disease (AD) and aging. Thus, the chronic treatment with AZP2006 was shown to reduce the loss of central synapses and neurons but also to dramatically decrease the massive neuroinflammation associated with the animal pathology. A deeper investigation showed that the beneficial effects of AZP2006 were associated with PGRN production. Also, AZP2006 binds to PSAP (the cofactor of PGRN) and inhibits TLR9 receptors normally responsible for proinflammation when activated. Altogether, these results showed the high potential of AZP2006 as a new putative treatment for AD and related diseases.

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Direct interaction of the extracellular matrix protein DANCE with apolipoprotein(a) mediated by the kringle IV-type 2 domain

Molecular Genetics and Genomics ◽

10.1007/s00438-002-0673-6 ◽

2002 ◽

Vol 267 (4) ◽

pp. 440-446 ◽

Cited By ~ 21

Author(s):

A. Kapetanopoulos ◽

F. Fresser ◽

G. Millonig ◽

Y. Shaul ◽

G. Baier ◽

...

Keyword(s):

Extracellular Matrix ◽

Matrix Protein ◽

Direct Interaction ◽

Extracellular Matrix Protein ◽

Apolipoprotein A

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MiR-137 promotes cell growth and inhibits extracellular matrix protein expression in H2O2-induced human trabecular meshwork cells by targeting Src

Neuroscience Letters ◽

10.1016/j.neulet.2021.135902 ◽

2021 ◽

Vol 755 ◽

pp. 135902

Author(s):

Liang Wang ◽

Ying Tian ◽

Yan Cao ◽

Qiang Ma ◽

Shuai Zhao

Keyword(s):

Extracellular Matrix ◽

Cell Growth ◽

Protein Expression ◽

Trabecular Meshwork ◽

Matrix Protein ◽

Extracellular Matrix Protein ◽

Trabecular Meshwork Cells

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Specific heparan sulfate modifications stabilize the synaptic organizer MADD-4/Punctin at C. elegans neuromuscular junctions

Genetics ◽

10.1093/genetics/iyab073 ◽

2021 ◽

Author(s):

Mélissa Cizeron ◽

Laure Granger ◽

Hannes E BÜlow ◽

Jean-Louis Bessereau

Keyword(s):

Heparan Sulfate ◽

Matrix Protein ◽

Neuromuscular Junctions ◽

Core Protein ◽

Extracellular Matrix Protein ◽

Inhibitory Synapses ◽

Single Chain ◽

C Elegans ◽

Sugar Chains

Abstract Heparan sulfate proteoglycans contribute to the structural organization of various neurochemical synapses. Depending on the system, their role involves either the core protein or the glycosaminoglycan chains. These linear sugar chains are extensively modified by heparan sulfate modification enzymes, resulting in highly diverse molecules. Specific modifications of glycosaminoglycan chains may thus contribute to a sugar code involved in synapse specificity. Caenorhabditis elegans is particularly useful to address this question because of the low level of genomic redundancy of these enzymes, as opposed to mammals. Here, we systematically mutated the genes encoding heparan sulfate modification enzymes in C. elegans and analyzed their impact on excitatory and inhibitory neuromuscular junctions. Using single chain antibodies that recognize different heparan sulfate modification patterns, we show in vivo that these two heparan sulfate epitopes are carried by the SDN-1 core protein, the unique C. elegans syndecan orthologue, at neuromuscular junctions. Intriguingly, these antibodies differentially bind to excitatory and inhibitory synapses, implying unique heparan sulfate modification patterns at different neuromuscular junctions. Moreover, while most enzymes are individually dispensable for proper organization of neuromuscular junctions, we show that 3-O-sulfation of SDN-1 is required to maintain wild-type levels of the extracellular matrix protein MADD-4/Punctin, a central synaptic organizer that defines the identity of excitatory and inhibitory synaptic domains at the plasma membrane of muscle cells.

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