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Prothrombin is a binding partner of the human Receptor of Advanced Glycation End products

ABSTRACT: The receptor for advanced glycation end products (RAGE) plays a key role in mammal physiology and in the etiology and progression of inflammatory and oxidative stress-based diseases. In adults, RAGE expression is high only in the lung where the protein concentrates in the basal membrane of Type I alveolar epithelial cells. In diseases, RAGE levels increase in the affected tissues and sustain chronic inflammation. RAGE exists as a single trans-membrane protein with an ectodomain and a short carboxyl-terminal tail essential for signaling, or also as a soluble ectodomain (sRAGE) that acts as a decoy receptor. The ectodomain is composed of a variable and two constant IgG-like domains (V, C1 and C2). VC1 is a single integrated unit responsible for binding of RAGE to the majority of its ligands including the advanced glycation End products (AGEs), S100 proteins and HMGB-1. Here, we report the identification of 20 new RAGE binding partners captured from human plasma and involved in the coagulation and complement processes and in the extracellular matrix. Four proteins contained a -carboxyl glutamic acid (Gla)-domain. Using MicroScale Thermophoresis, we quantified the interaction of prothrombin (PT) with VC1 and with sRAGE. Calcium competed in the binding of PT to sRAGE and PT devoid of the Gla-domain did not bind to sRAGE, providing evidence that the Gla-domain is critical for the interaction. Finally, the presence of VC1 delayed plasma clotting in a dose-dependent manner. We propose that RAGE is involved in modulating blood coagulation presumably in conditions of lung injury.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Plasma

SUBMITTER: Alessandra Altomare

LAB HEAD: Alessandra Altomare

PROVIDER: PXD020355 | Pride | 2020-07-14

REPOSITORIES: pride

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Project description:Burgeoning evidence highlights seminal roles for microglia in the pathogenesis of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). The receptor for advanced glycation end products (RAGE) binds ligands relevant to ALS that accumulate in the diseased spinal cord and RAGE has been previously implicated in the progression of ALS pathology. We generated a novel mouse model to temporally delete Ager from microglia in the murine SOD1G93A model of ALS. Microglia Ager deficient SOD1G93A mice and controls were examined for changes in survival, motor function, gliosis, motor neuron numbers, and transcriptomic analyses of lumbar spinal cord. Furthermore, we examined bulk-RNA-sequencing transcriptomic analyses of human ALS cervical spinal cord. Transcriptomic analysis of human cervical spinal cord reveals a range of AGER expression in ALS patients, which was negatively correlated with age at disease onset and death or tracheostomy. The degree of AGER expression related to differential expression of pathways involved in extracellular matrix, lipid metabolism, and intercellular communication. Microglia display increased RAGE immunoreactivity in the spinal cords of high AGER expressing patients and in the SOD1G93A murine model of ALS vs. respective controls. We demonstrate that microglia Ager deletion at the age of symptomatic onset, day 90, in SOD1G93A mice extends survival in male but not female mice. Critically, many of the pathways identified in human ALS patients that accompanied increased AGER expression were significantly ameliorated by microglia Ager deletion in male SOD1G93A mice. Our results indicate that microglia RAGE disrupts communications with cell types including astrocytes and neurons, intercellular communication pathways that divert microglia from a homeostatic to an inflammatory and tissue-injurious program. In totality, microglia RAGE contributes to the progression of SOD1G93A murine pathology in male mice and may be relevant in human disease.

			Action	DRS
	Spot25_Exp4_Sample8.RAW	Raw
	Spot25_Exp4_Sample8.msf	Msf
	Spot26_Exp4_Sample8.RAW	Raw
	Spot26_Exp4_Sample8.msf	Msf
	Spot37_Exp4_Sample8.RAW	Raw

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Prothrombin is a binding partner of the human Receptor of Advanced Glycation End products

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