scholarly journals Crystal structure of the SH3 domain of growth factor receptor-bound protein 2

2020 ◽  
Vol 76 (6) ◽  
pp. 263-270
Author(s):  
Alexandr Bolgov ◽  
Svetlana Korban ◽  
Dmitrii Luzik ◽  
Vladimir Zhemkov ◽  
Meewhi Kim ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Growth Factor ◽  
Cell Communication ◽  
Growth Factor Receptor ◽  
Adaptor Protein ◽  
Full Length ◽  
New Information ◽  
Carboxy Terminal Region ◽  
Carboxy Terminal ◽  
Growth Factor Receptor Bound

This study presents the crystal structure of the N-terminal SH3 (SH3N) domain of growth factor receptor-bound protein 2 (Grb2) at 2.5 Å resolution. Grb2 is a small (215-amino-acid) adaptor protein that is widely expressed and involved in signal transduction/cell communication. The crystal structure of full-length Grb2 has previously been reported (PDB entry 1gri). The structure of the isolated SH3N domain is consistent with the full-length structure. The structure of the isolated SH3N domain was solved at a higher resolution (2.5 Å compared with 3.1 Å for the previously deposited structure) and made it possible to resolve some of the loops that were missing in the full-length structure. In addition, interactions between the carboxy-terminal region of the SH3N domain and the Sos1-binding sites were observed in the structure of the isolated domain. Analysis of these interactions provided new information about the ligand-binding properties of the SH3N domain of Grb2.

scholarly journals Dysfunction of GRAP, encoding the GRB2-related adaptor protein, is linked to sensorineural hearing loss

2019 ◽  
Vol 116 (4) ◽  
pp. 1347-1352 ◽  
Author(s):  
Chong Li ◽  
Guney Bademci ◽  
Asli Subasioglu ◽  
Oscar Diaz-Horta ◽  
Yi Zhu ◽  
...  
Keyword(s):  
Growth Factor ◽  
Growth Factor Receptor ◽  
Adaptor Protein ◽  
Adaptor Proteins ◽  
Ras Signaling ◽  
Nonsyndromic Deafness ◽  
Auditory Hair Cells ◽  
Cytoskeleton Dynamics ◽  
Growth Factor Receptor Bound

We have identified a GRAP variant (c.311A>T; p.Gln104Leu) cosegregating with autosomal recessive nonsyndromic deafness in two unrelated families. GRAP encodes a member of the highly conserved growth factor receptor-bound protein 2 (GRB2)/Sem-5/drk family of proteins, which are involved in Ras signaling; however, the function of the growth factor receptor-bound protein 2 (GRB2)-related adaptor protein (GRAP) in the auditory system is not known. Here, we show that, in mouse, Grap is expressed in the inner ear and the protein localizes to the neuronal fibers innervating cochlear and utricular auditory hair cells. Downstream of receptor kinase (drk), the Drosophila homolog of human GRAP, is expressed in Johnston’s organ (JO), the fly hearing organ, and the loss of drk in JO causes scolopidium abnormalities. drk mutant flies present deficits in negative geotaxis behavior, which can be suppressed by human wild-type but not mutant GRAP. Furthermore, drk specifically colocalizes with synapsin at synapses, suggesting a potential role of such adaptor proteins in regulating actin cytoskeleton dynamics in the nervous system. Our findings establish a causative link between GRAP mutation and nonsyndromic deafness and suggest a function of GRAP/drk in hearing.

scholarly journals How IGF-1 activates its receptor

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Jennifer M Kavran ◽  
Jacqueline M McCabe ◽  
Patrick O Byrne ◽  
Mary Katherine Connacher ◽  
Zhihong Wang ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Growth Factor ◽  
Ligand Binding ◽  
Insulin Receptor ◽  
Conformational Change ◽  
Growth Factor Receptor ◽  
Full Length ◽  
Type I ◽  
Insulin Like Growth Factor ◽  
Growth And Survival

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. Ligand binding releases this constraint, allowing TM association and unleashing an intrinsic propensity of the intracellular regions to autophosphorylate. Enzymatic studies of full-length and kinase-containing fragments show phosphorylated IGF1R is fully active independent of ligand and the extracellular-TM regions. The key step triggered by ligand binding is thus autophosphorylation.

Human growth factor receptor bound 14 binds the activated insulin receptor and alters the insulin-stimulated tyrosine phosphorylation levels of multiple proteins

2001 ◽  
Vol 79 (1) ◽  
pp. 21-32 ◽  
Author(s):  
Richard Hemming ◽  
Ronald Agatep ◽  
Ketan Badiani ◽  
Kerrie Wyant ◽  
Gilbert Arthur ◽  
...  
Keyword(s):  
Growth Factor ◽  
Insulin Receptor ◽  
Tyrosine Phosphorylation ◽  
Insulin Signaling ◽  
Growth Factor Receptor ◽  
Adaptor Protein ◽  
Human Growth ◽  
Yeast Two Hybrid System ◽  
Growth Factor Receptor Bound ◽  
Two Hybrid

To identify proteins interacting in the insulin-signaling pathway that might define new pathways or regulate existing ones, we have employed the yeast two-hybrid system. In a two-hybrid screen of a human liver cDNA library, we identified the human growth factor receptor bound 14 (hGrb14) adaptor protein as a partner of the activated insulin receptor. Additional analysis of the insulin receptor - hGrb14 interaction in the yeast two-hybrid system revealed that the SH2 domain of hGrb14 was not the sole region involved in binding the activated insulin receptor. The insulin-stimulated interaction between hGrb14 and the insulin receptor was also observed in different mammalian cultured cell lines. This association was detected at 1 min of insulin stimulation and was maximal at 10 nM and greater concentrations of insulin. Chinese hamster ovary cells stably expressing the insulin receptor (CHO-IR) and hGrb14 were used to examine the effects of hGrb14 overexpression on insulin-stimulated tyrosine phosphorylation of proteins; in general, increasing levels of hGrb14 expression resulted in a reduction in tyrosine phosphorylation. This decrease was demonstrated for the specific proteins src homology-containing and collagen-related protein (Shc), insulin receptor substrate-1 (IRS-1), and Downstream of tyrosine Kinase (Dok). The broad effects of hGrb14 overexpression on insulin-stimulated tyrosine phosphorylation suggest that it acts early in the insulin-signaling pathway.Key words: insulin signaling, growth factor receptor bound 14, Grb14, adaptor protein, insulin receptor.

Occurrence of GRB10 (+11275G > A) polymorphism in Hungarian population and its relationship to glucose metabolism

2009 ◽  
Vol 150 (40) ◽  
pp. 1845-1851 ◽  
Author(s):  
Márta Vitai ◽  
Barbara Buday ◽  
Enikő Kulcsár ◽  
Botond Literáti-Nagy ◽  
Istvánné Vecsei ◽  
...  
Keyword(s):  
Growth Factor ◽  
Glucose Metabolism ◽  
Growth Factor Receptor ◽  
Hungarian Population ◽  
Growth Factor Receptor Bound

Az előkísérletünk során az egészséges és spontán hipertóniás patkányok között génexpressziós különbségeket találtunk „differencial display” eljárással. Az eltérően expresszált gének között szerepelt a GRB10 gén, amelynek terméke a GRB10 (Growth factor receptor-bound protein) fehérje. A GRB10 protein kötődik az inzulinreceptorokhoz, negatív regulátorproteinként tartják számon és polimorfizmusait összefüggésbe hozták a 2-es típusú diabétesz kialakulásával. Vizsgálatunk során a GRB10 gén +11275G > A(RS 2237457) polimorfizmusát vizsgáltuk magyarországi 2-es típusú cukorbetegek és egészségesek esetében (2DM-es beteg n = 85, egészséges kontroll n = 77). Kerestük az összefüggéseket a genotípus és a hyperinsulinaemiás-normoglykaemiás clamp vizsgálattal mért, a glükózhomeosztázisra jellemző paraméterek között egészséges (n = 88) és glükózintoleráns (IFG n = 15; IGT n = 29 és kezelést nem igénylő 2-es típusú diabéteszes: n = 9) betegek esetében. A hazai populációban nem találtunk szignifikáns különbséget az allélgyakoriság között az egészséges és a 2DM-csoport között (egészséges g vs. a: 62% vs. 38%; 2DM g vs. a: 70% vs. 30%). Az inzulinérzékenységet tükröző glükózfelhasználás nők esetében nem függött a GRB10 gén polimorfizmusától. Férfiak esetében a gg polimorfizmus az OGTT glükózterhelés során fokozott, de az ivGTT-terhelés során azonos mértékű inzulinelválasztással társult. Férfiakban gg allél esetében alacsonyabb az izomtömeg glükózfelhasználása, az egész test és az izomszövet vonatkozásában a glükózeltűnési ráta, és mindkét nemben rosszabb a lipidprofil, alacsonyabb a kisebb denzitású, nagyobb molekulájú LDL-frakciók koncentrációja, nők esetében pedig a HDL-koleszterin-vérszint. A GRB10 génpolimorfizmussal kapcsolatos anyagcsere-eltérések alátámasztják – a „prediabéteszes” időszakban – a génnek az inzulinérzékenységben és inzulinelválasztásban feltételezett szerepét, amely azonban nemhez kötött és csak férfiakban észlelhető. A po. és iv. cukorterhelés alatt mért inzulinelválasztási eltérések alapján felvethető, hogy a GRB10 gén az inkretin jelátvitelben is szerepet játszik.

scholarly journals Crystal structure of the kinase domain of human vascular endothelial growth factor receptor 2: a key enzyme in angiogenesis

Structure ◽  
1999 ◽  
Vol 7 (3) ◽  
pp. 319-330 ◽  
Author(s):  
Michele A McTigue ◽  
John A Wickersham ◽  
Chris Pinko ◽  
Richard E Showalter ◽  
Camran V Parast ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Growth Factor Receptor ◽  
Kinase Domain ◽  
Vascular Endothelial ◽  
Key Enzyme ◽  
Endothelial Growth Factor
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