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Sarvenaz Sarabipour

Sarvenaz Sarabipour, Feilim Mac Gabhann
No abstract text is available yet for this article.
January 9, 2018: Biochemistry
Sarvenaz Sarabipour, Feilim Mac Gabhann
All known splice isoforms of vascular endothelial growth factor A (VEGF-A) can bind to the receptor tyrosine kinases VEGFR-1 and VEGFR-2. We focus here on VEGF-A121a and VEGF-A165a, two of the most abundant VEGF-A splice isoforms in human tissue 1 , and their ability to bind the Neuropilin co-receptors NRP1 and NRP2. The Neuropilins are key vascular, immune, and nervous system receptors on endothelial cells, neuronal axons, and regulatory T cells respectively. They serve as co-receptors for the Plexins in Semaphorin binding on neuronal and vascular endothelial cells, and for the VEGFRs in VEGF binding on vascular and lymphatic endothelial cells, and thus regulate the initiation and coordination of cell signaling by Semaphorins and VEGFs...
November 2, 2017: Cell Adhesion & Migration
Sarvenaz Sarabipour
Receptor tyrosine kinase (RTK) signal transduction is essential in human skeletal, nervous, and vascular development, in homeostasis, and in disease. RTKs are activated by dimerization in the plasma membrane. The mechanisms of receptor dimerization and activation are multifaceted and complex, and unraveling them remains challenging. Most studies of RTKs have been devoted to crystallographic analysis of their isolated extracellular domain and biochemical analysis of the catalytic domain. However, the past few years have seen direct biophysical studies of (intact) RTK dimerization in native membranes lead to significant progress in our fundamental understanding of the mechanisms of their signal transduction across the plasma membrane...
June 27, 2017: Biochemistry
Deo R Singh, Fozia Ahmed, Sarvenaz Sarabipour, Kalina Hristova
Epithelial cadherin (Ecadherin) is responsible for the intercellular cohesion of epithelial tissues. It forms lateral clusters within adherens cell-cell junctions, but its association state outside these clusters is unknown. Here, we use a quantitative Forster resonance energy transfer (FRET) approach to show that Ecadherin forms constitutive dimers and that these dimers exist independently of the actin cytoskeleton or cytoplasmic proteins. The dimers are stabilized by intermolecular contacts that occur along the entire length of Ecadherin, with the intracellular domains having a surprisingly strong favorable contribution...
July 7, 2017: Journal of Molecular Biology
Nuala Del Piccolo, Sarvenaz Sarabipour, Kalina Hristova
The activity of receptor tyrosine kinases (RTKs) is controlled through their lateral association in the plasma membrane. RTKs are believed to form both homodimers and heterodimers, and the different dimers are believed to play unique roles in cell signaling. However, RTK heterodimers remain poorly characterized, as compared with homodimers, because of limitations in current experimental methods. Here, we develop a FRET-based methodology to assess the thermodynamics of hetero-interactions in the plasma membrane...
January 27, 2017: Journal of Biological Chemistry
Sarvenaz Sarabipour, Kalina Hristova
Missense mutations that introduce or remove cysteine residues in receptor tyrosine kinases are believed to cause pathologies by stabilizing the active receptor tyrosine kinase dimers. However, the magnitude of this stabilizing effect has not been measured for full-length receptors. Here, we characterize the dimer stabilities of three full-length fibroblast growth factor receptor (FGFR) mutants harboring pathogenic cysteine substitutions: the C178S FGFR1 mutant, the C342R FGFR2 mutant, and the C228R FGFR3 mutant...
October 9, 2016: Journal of Molecular Biology
Sarvenaz Sarabipour, Kurt Ballmer-Hofer, Kalina Hristova
VEGFR-2 is the primary regulator of angiogenesis, the development of new blood vessels from pre-existing ones. VEGFR-2 has been hypothesized to be monomeric in the absence of bound ligand, and to undergo dimerization and activation only upon ligand binding. Using quantitative FRET and biochemical analysis, we show that VEGFR-2 forms dimers also in the absence of ligand when expressed at physiological levels, and that these dimers are phosphorylated. Ligand binding leads to a change in the TM domain conformation, resulting in increased kinase domain phosphorylation...
April 7, 2016: ELife
Sarvenaz Sarabipour, Kalina Hristova
The G380R mutation in the transmembrane domain of FGFR3 is a germline mutation responsible for most cases of Achondroplasia, a common form of human dwarfism. Here we use quantitative Fӧster Resonance Energy Transfer (FRET) and osmotically derived plasma membrane vesicles to study the effect of the achondroplasia mutation on the early stages of FGFR3 signaling in response to the ligands fgf1 and fgf2. Using a methodology that allows us to capture structural changes on the cytoplasmic side of the membrane in response to ligand binding to the extracellular domain of FGFR3, we observe no measurable effects of the G380R mutation on FGFR3 ligand-bound dimer configurations...
July 2016: Biochimica et Biophysica Acta
Sarvenaz Sarabipour, Kalina Hristova
Fibroblast growth factors (fgfs) are widely believed to activate their receptors by mediating receptor dimerization. Here we show, however, that the FGF receptors form dimers in the absence of ligand, and that these unliganded dimers are phosphorylated. We further show that ligand binding triggers structural changes in the FGFR dimers, which increase FGFR phosphorylation. The observed effects due to the ligands fgf1 and fgf2 are very different. The fgf2-bound dimer structure ensures the smallest separation between the transmembrane (TM) domains and the highest possible phosphorylation, a conclusion that is supported by a strong correlation between TM helix separation in the dimer and kinase phosphorylation...
2016: Nature Communications
Sarvenaz Sarabipour, Nuala Del Piccolo, Kalina Hristova
Here we describe an experimental tool, termed quantitative imaging Förster resonance energy transfer (QI-FRET), that enables the quantitative characterization of membrane protein interactions. The QI-FRET methodology allows us to acquire binding curves and calculate association constants for complex membrane proteins in the native plasma membrane environment. The method utilizes FRET detection, and thus requires that the proteins of interest are labeled with florescent proteins, either FRET donors or FRET acceptors...
August 18, 2015: Accounts of Chemical Research
Sarvenaz Sarabipour, Kalina Hristova
Receptor tyrosine kinases (RTKs) conduct biochemical signals upon dimerization in the membrane plane. While RTKs are generally known to be activated in response to ligand binding, many of these receptors are capable of forming unliganded dimers that are likely important intermediates in the signaling process. All 58 RTKs consist of an extracellular (EC) domain, a transmembrane (TM) domain, and an intracellular domain that includes a juxtamembrane (JM) sequence and a kinase domain. Here we investigate directly the effect of the JM domain on unliganded dimer stability of FGFR3, a receptor that is critically important for skeletal development...
April 24, 2015: Journal of Molecular Biology
Jennifer M Kavran, Jacqueline M McCabe, Patrick O Byrne, Mary Katherine Connacher, Zhihong Wang, Alexander Ramek, Sarvenaz Sarabipour, Yibing Shan, David E Shaw, Kalina Hristova, Philip A Cole, Daniel J Leahy
The type I insulin-like growth factor receptor (IGF1R) is involved in growth and survival of normal and neoplastic cells. A ligand-dependent conformational change is thought to regulate IGF1R activity, but the nature of this change is unclear. We point out an underappreciated dimer in the crystal structure of the related Insulin Receptor (IR) with Insulin bound that allows direct comparison with unliganded IR and suggests a mechanism by which ligand regulates IR/IGF1R activity. We test this mechanism in a series of biochemical and biophysical assays and find the IGF1R ectodomain maintains an autoinhibited state in which the TMs are held apart...
2014: ELife
Christopher King, Sarvenaz Sarabipour, Patrick Byrne, Daniel J Leahy, Kalina Hristova
Förster resonance energy transfer (FRET) experiments are often used to study interactions between integral membrane proteins in cellular membranes. However, in addition to the FRET of sequence-specific interactions, these experiments invariably record a contribution due to proximity FRET, which occurs when a donor and an acceptor approach each other by chance within distances of ∼100 Å. This effect does not reflect specific interactions in the membrane and is frequently unappreciated, despite the fact that its magnitude can be significant...
March 18, 2014: Biophysical Journal
Sarvenaz Sarabipour, Christopher King, Kalina Hristova
Here we introduce a fast, cost-effective, and highly efficient method for production of soluble fluorescent proteins from bacteria. The method does not require optimization and does not use isopropyl β-d-1-thiogalactopyranoside (IPTG) induction. The method relies on uninduced expression in the BL21-Gold (DE3) strain of Escherichia coli and yields large amounts (up to 0.4 μmol) of fluorescent protein from a 250-ml culture. This method is much simpler than published methods and can be used to produce any fluorescent protein that is needed in biomedical research...
March 15, 2014: Analytical Biochemistry
Sarvenaz Sarabipour, Kalina Hristova
Isolated receptor tyrosine kinase transmembrane (TM) domains have been shown to form sequence-specific dimers in membranes. Yet, it is not clear whether studies of isolated TM domains yield knowledge that is relevant to full-length receptors or whether the large glycosylated extracellular domains alter the interactions between the TM helices. Here, we address this question by quantifying the effect of the pathogenic A391E TM domain mutation on the stability of the fibroblast growth factor receptor 3 dimer in the presence of the extracellular domain and comparing these results to the case of the isolated TM fibroblast growth factor receptor 3 domains...
July 2, 2013: Biophysical Journal
Sarvenaz Sarabipour, Kalina Hristova
Membrane protein interactions, which underlie biological function, take place in the complex cellular membrane environment. Plasma membrane derived vesicles are a model system which allows the interactions between membrane proteins to be studied without the need for their extraction, purification, and reconstitution into lipid bilayers. Plasma membrane vesicles can be produced from different cell lines and by different methods, providing a rich variety of native-like model systems. With these choices, however, questions arise as to how the different types of vesicle preparations affect the interactions between membrane proteins...
August 2013: Biochimica et Biophysica Acta
Fenghao Chen, Sarvenaz Sarabipour, Kalina Hristova
The A391E mutation in fibroblast growth factor receptor 3 (FGFR3) is the genetic cause for Crouzon syndrome with Acanthosis Nigricans. Here we investigate the effect of this mutation on FGFR3 activation in HEK 293 T cells over a wide range of fibroblast growth factor 1 concentrations using a physical-chemical approach that deconvolutes the effects of the mutation on dimerization, ligand binding, and efficiency of phosphorylation. It is believed that the mutation increases FGFR3 dimerization, and our results verify this...
2013: PloS One
Stephen G Bosi, Saxby Brown, Sarvenaz Sarabipour, Yves De Deene, Clive Baldock
A gelatin phantom containing an optically scattering funnel-shaped region of elevated optical density (OD) was used to examine light-scattering-induced artefacts in a cone-beam optical CT scanner used for gel dosimetry. To simulate polymer gel dosimeters, the opacity was introduced by adding a colloidal scatterer to the gelatin. Scatter results in an underestimate of OD (hence dose). In line profiles of OD taken from 3D reconstructions of the funnel, those profiles with a long pathlength through high OD regions exhibited a 'dishing' (or 'cupping') artefact, while those of short pathlength exhibited the opposite effect-'doming'...
January 21, 2009: Physics in Medicine and Biology
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