COMP-Ang1: A designed angiopoietin-1 variant with nonleaky angiogenic activity

Cho, Chung Hyun; Kammerer, Richard A.; Lee, Hyuek Jong; Steinmetz, Michel O.; Ryu, Young Shin; Lee, Sung Ho; Yasunaga, Kunio; Kim, Young Ho; Kim, Injune; Choi, Han Ho; Kim, Won; Kim, Sung Hyun; Park, Sung Kwang; Lee, Gyun Min; Koh, Gou Young

doi:10.1073/pnas.0307574101

Cited by 235 publications

(262 citation statements)

References 33 publications

Supporting

Mentioning

254

Contrasting

Unclassified

Order By: Relevance

“…Detailed knowledge of the folding mechanisms of coiled coils is crucial for exploiting their potential in a wide range of applications and understanding their functions in a large number of biological processes (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(21)(22)(23)(24). Here, we use the GCN4 leucine zipper as a model system to investigate fundamental principles underlying coiled-coil formation.…”

Section: Discussionmentioning

confidence: 99%

“…A need for a detailed understanding of coiled-coil folding is relevant, particularly in light of the important functions these structures play in almost all biological processes, as well as the considerable attention coiled coils have recently garnered in a wide range of applications, including basic research, nanomaterials, protein engineering, biotechnology, and medicine (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13). Furthermore, understanding the folding mechanisms of coiled coils is of fundamental interest to experimentalists and theoreticians challenged by the question of how the sequence of a protein defines its specific 3D structure.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Molecular basis of coiled-coil formation

Steinmetz

Jelesarov

Matousek

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

121

126

View full text Add to dashboard Cite

Coiled coils have attracted considerable interest as design templates in a wide range of applications. Successful coiled-coil design strategies therefore require a detailed understanding of coiled-coil folding. One common feature shared by coiled coils is the presence of a short autonomous helical folding unit, termed ''trigger sequence,'' that is indispensable for folding. Detailed knowledge of trigger sequences at the molecular level is thus key to a general understanding of coiled-coil formation. Using a multidisciplinary approach, we identify and characterize here the molecular determinants that specify the helical conformation of the monomeric early folding intermediate of the GCN4 coiled coil. We demonstrate that a network of hydrogen-bonding and electrostatic interactions stabilize the trigger-sequence helix. This network is rearranged in the final dimeric coiled-coil structure, and its destabilization significantly slows down GCN4 leucine zipper folding. Our findings provide a general explanation for the molecular mechanism of coiled-coil formation.autonomous folding unit ͉ protein folding ͉ trigger sequence ͉ leucine zipper ͉ ␣-helix A lthough coiled coils have been used traditionally as model systems for protein folding studies, the molecular basis of how they fold is still largely unknown. A need for a detailed understanding of coiled-coil folding is relevant, particularly in light of the important functions these structures play in almost all biological processes, as well as the considerable attention coiled coils have recently garnered in a wide range of applications, including basic research, nanomaterials, protein engineering, biotechnology, and medicine (1-13). Furthermore, understanding the folding mechanisms of coiled coils is of fundamental interest to experimentalists and theoreticians challenged by the question of how the sequence of a protein defines its specific 3D structure. Along these lines, we have been interested particularly in coiled-coil ''trigger sequences,'' which encode stable monomeric ␣-helices that are indispensable for coiled-coil formation (14-18). Although there are a few examples of synthetic peptides that fold either into heterodimers (19) or at conditions of extremes of pH (20) without an apparent trigger sequence, the ''trigger site'' concept is generally accepted because these short autonomous helical folding units are structurally and functionally conserved in a large number of native coiled-coil proteins (reviewed in refs. 21-24). Detailed knowledge of the properties of trigger sequences at the molecular level is therefore key to an understanding of coiled-coil formation and function in general.The parallel two-stranded leucine zipper of the yeast transcriptional activator GCN4 is the best-characterized coiled coil and thus represents an excellent paradigm for a comprehensive analysis of the roles of trigger sequences in coiled-coil folding. Our current understanding of the folding kinetics of the GCN4 leucine zipper is based on extensive stopped-flow studies and te...

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Molecular basis of coiled-coil formation

Steinmetz

Jelesarov

Matousek

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

121

126

View full text Add to dashboard Cite

show abstract

“…Antibodies used in this study were as follows: YAP (Santa Cruz Biotechnology, sc-101199; Cell Signaling, #4912), phospho-YAP (S127, Cell Signaling, #4911), ANG-2 (R&D Systems, MAB0983 or AF623), CDH5 (BD Transduction Laboratories, #610251), Akt (#3787), Phospho-Akt (#9271), LATS1 (#9153), phospho-LATS1 (S909) (#9157; Cell Signaling), LATS2 (Bethyl Laboratories, #A300-479A) and b-actin (Santa Cruz Biotechnology). COMP-ANG-1 was generously provided by Dr Koh 43 . PI3K inhibitor, Ly294002 (L9908), and human thrombin (T7009) were purchased from Sigma.…”

Section: Methodsmentioning

confidence: 99%

Yes-associated protein regulates endothelial cell contact-mediated expression of angiopoietin-2

et al. 2015

View full text Add to dashboard Cite

Angiogenesis is regulated by the dynamic interaction between endothelial cells (ECs).Hippo-Yes-associated protein (YAP) signalling has emerged as a key pathway that controls organ size and tissue growth by mediating cell contact inhibition. However, the role of YAP in EC has not been defined yet. Here, we show expression of YAP in the developing front of mouse retinal vessels. YAP subcellular localization, phosphorylation and activity are regulated by VE-cadherin-mediated-EC contacts. This VE-cadherin-dependent YAP phosphorylation requires phosphoinositide 3-kinase-Akt activation. We further identify angiopoietin-2 (ANG-2) as a potential transcriptional target of YAP in regulating angiogenic activity of EC in vitro and in vivo. Overexpression of YAP-active form in EC enhances angiogenic sprouting, and this effect is blocked by ANG-2 depletion or soluble Tie-2 treatment. These findings implicate YAP as a critical regulator in angiogenesis and provide new insights into the mechanism coordinating junctional stability and angiogenic activation of ECs.

show abstract

“…We have produced COMP-Ang1 as previously described (Cho et al, 2004a;Hwang et al, 2005). COMP-Ang1 (0.1, 0.5, or 1 mg/kg) suspended in PBS (vehicle control) was administered i.v.…”

Section: Administration Of Comp-ang1mentioning

confidence: 99%

Blockade of airway inflammation and hyper-responsiveness by an angiopoietin-1 variant, COMP-Ang1

Lee

Lee²,

Kim³

et al. 2007

Exp Mol Med

Self Cite

View full text Add to dashboard Cite

Inflammation of the asthmatic airway is usually accompanied by increased vascular permeability and plasma exudation. Angiopoietin-1 (Ang1) has potential therapeutic applications in preventing vascular leakage. Recently, we developed a soluble, stable, and potent Ang1 variant, COMP-Ang1. COMP-Ang1 is more potent than native Ang1 in phosphorylating the tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 receptor in lung endothelial cells. We have used a mouse model for allergic airway disease to determine effects of COMP-Ang1 on allergen-induced bronchial inflammation and airway hyper-responsiveness. These mice develop the following typical pathophysiological features of allergic airway disease in the lungs: increased numbers of inflammatory cells of the airways, airway hyper-responsiveness, increased levels of Th2 cell cytokines (IL-4, IL-5, and IL-13), adhesion molecules (intercellular adhesion molecule-1 and vascular cell adhesion molecule-1), and chemokines (eotaxin and RANTES), and increased vascular permeability. Intravenous administration of COMP-Ang1 reduced bronchial inflammation and airway hyper-responsiveness. In addition, the increased plasma extravasation in allergic airway disease was significantly reduced by the administration of COMP-Ang1. These results suggest that COMP-Ang1 attenuates airway inflammation and hyper-responsiveness, prevents vascular leakage, and may be used as a therapeutic agent in allergic airway disease.

show abstract

COMP-Ang1: A designed angiopoietin-1 variant with nonleaky angiogenic activity

Cited by 235 publications

References 33 publications

Molecular basis of coiled-coil formation

Molecular basis of coiled-coil formation

Yes-associated protein regulates endothelial cell contact-mediated expression of angiopoietin-2

Blockade of airway inflammation and hyper-responsiveness by an angiopoietin-1 variant, COMP-Ang1

Contact Info

Product

Resources

About