scholarly journals The prodomain of BMP4 is necessary and sufficient to generate stable BMP4/7 heterodimers with enhanced bioactivity in vivo

2015 ◽  
Vol 112 (18) ◽  
pp. E2307-E2316 ◽  
Author(s):  
Judith M. Neugebauer ◽  
Sunjong Kwon ◽  
Hyung-Seok Kim ◽  
Nathan Donley ◽  
Anup Tilak ◽  
...  
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Clinical Implications ◽  
Intrinsic Properties ◽  
Enhanced Activity ◽  
Bone Injury ◽  
Precursor Proteins ◽  
Necessary And Sufficient ◽  
Signaling Activity ◽  
Bioactive Ligand

Bone morphogenetic proteins 4 and 7 (BMP4 and BMP7) are morphogens that signal as either homodimers or heterodimers to regulate embryonic development and adult homeostasis. BMP4/7 heterodimers exhibit markedly higher signaling activity than either homodimer, but the mechanism underlying the enhanced activity is unknown. BMPs are synthesized as inactive precursors that dimerize and are then cleaved to generate both the bioactive ligand and prodomain fragments, which lack signaling activity. Our study reveals a previously unknown requirement for the BMP4 prodomain in promoting heterodimer activity. We show that BMP4 and BMP7 precursor proteins preferentially or exclusively form heterodimers when coexpressed in vivo. In addition, we show that the BMP4 prodomain is both necessary and sufficient for generation of stable heterodimeric ligands with enhanced activity and can enable homodimers to signal in a context in which they normally lack activity. Our results suggest that intrinsic properties of the BMP4 prodomain contribute to the relative bioactivities of homodimers versus heterodimers in vivo. These findings have clinical implications for the use of BMPs as regenerative agents for the treatment of bone injury and disease.

scholarly journals NK cell activation through the NKG2D ligand MULT-1 is selectively prevented by the glycoprotein encoded by mouse cytomegalovirus gene m145

2005 ◽  
Vol 201 (2) ◽  
pp. 211-220 ◽  
Author(s):  
Astrid Krmpotic ◽  
Milena Hasan ◽  
Andrea Loewendorf ◽  
Tanja Saulig ◽  
Anne Halenius ◽  
...  
Keyword(s):  
Cell Activation ◽  
Nk Cell ◽  
Surface Expression ◽  
Viral Gene ◽  
Nkg2d Ligand ◽  
Mouse Cytomegalovirus ◽  
Mcmv Infection ◽  
Viral Survival ◽  
Necessary And Sufficient

The NK cell–activating receptor NKG2D interacts with three different cellular ligands, all of which are regulated by mouse cytomegalovirus (MCMV). We set out to define the viral gene product regulating murine UL16-binding protein-like transcript (MULT)-1, a newly described NKG2D ligand. We show that MCMV infection strongly induces MULT-1 gene expression, but surface expression of this glycoprotein is nevertheless completely abolished by the virus. Screening a panel of MCMV deletion mutants defined the gene m145 as the viral regulator of MULT-1. The MCMV m145-encoded glycoprotein turned out to be necessary and sufficient to regulate MULT-1 by preventing plasma membrane residence of MULT-1. The importance of MULT-1 in NK cell regulation in vivo was confirmed by the attenuating effect of the m145 deletion that was lifted after NK cell depletion. Our findings underline the significance of escaping MULT-1/NKG2D signaling for viral survival and maintenance.

scholarly journals Bone Morphogenetic Proteins Are Required In Vivo for the Generation of Sympathetic Neurons

Neuron ◽  
1999 ◽  
Vol 24 (4) ◽  
pp. 861-870 ◽  
Author(s):  
Carolin Schneider ◽  
Helmut Wicht ◽  
Jana Enderich ◽  
Michael Wegner ◽  
Hermann Rohrer
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Sympathetic Neurons

scholarly journals A discrete pathway for the transfer of intermembrane space proteins across the outer membrane of mitochondria

2014 ◽  
Vol 25 (25) ◽  
pp. 3999-4009 ◽  
Author(s):  
Agnieszka Gornicka ◽  
Piotr Bragoszewski ◽  
Piotr Chroscicki ◽  
Lena-Sophie Wenz ◽  
Christian Schulz ◽  
...  
Keyword(s):  
Outer Membrane ◽  
Mitochondrial Membrane ◽  
Alternative Pathway ◽  
Intermembrane Space ◽  
Outer Mitochondrial Membrane ◽  
Membrane Translocation ◽  
Tom Complex ◽  
Precursor Proteins ◽  
Core Components

Mitochondrial proteins are synthesized on cytosolic ribosomes and imported into mitochondria with the help of protein translocases. For the majority of precursor proteins, the role of the translocase of the outer membrane (TOM) and mechanisms of their transport across the outer mitochondrial membrane are well recognized. However, little is known about the mode of membrane translocation for proteins that are targeted to the intermembrane space via the redox-driven mitochondrial intermembrane space import and assembly (MIA) pathway. On the basis of the results obtained from an in organello competition import assay, we hypothesized that MIA-dependent precursor proteins use an alternative pathway to cross the outer mitochondrial membrane. Here we demonstrate that this alternative pathway involves the protein channel formed by Tom40. We sought a translocation intermediate by expressing tagged versions of MIA-dependent proteins in vivo. We identified a transient interaction between our model substrates and Tom40. Of interest, outer membrane translocation did not directly involve other core components of the TOM complex, including Tom22. Thus MIA-dependent proteins take another route across the outer mitochondrial membrane that involves Tom40 in a form that is different from the canonical TOM complex.

scholarly journals The ER–Golgi intermediate compartment is a key membrane source for the LC3 lipidation step of autophagosome biogenesis

eLife ◽  
2013 ◽  
Vol 2 ◽  
Author(s):  
Liang Ge ◽  
David Melville ◽  
Min Zhang ◽  
Randy Schekman
Keyword(s):  
Autophagosome Formation ◽  
Functional Studies ◽  
A Cell ◽  
Intermediate Compartment ◽  
Membrane Isolation ◽  
Necessary And Sufficient ◽  
Organelle Membrane ◽  
Catabolic Process

Autophagy is a catabolic process for bulk degradation of cytosolic materials mediated by double-membraned autophagosomes. The membrane determinant to initiate the formation of autophagosomes remains elusive. Here, we establish a cell-free assay based on LC3 lipidation to define the organelle membrane supporting early autophagosome formation. In vitro LC3 lipidation requires energy and is subject to regulation by the pathways modulating autophagy in vivo. We developed a systematic membrane isolation scheme to identify the endoplasmic reticulum–Golgi intermediate compartment (ERGIC) as a primary membrane source both necessary and sufficient to trigger LC3 lipidation in vitro. Functional studies demonstrate that the ERGIC is required for autophagosome biogenesis in vivo. Moreover, we find that the ERGIC acts by recruiting the early autophagosome marker ATG14, a critical step for the generation of preautophagosomal membranes.

Niosomes for enhanced activity of praziquantel against Schistosoma mansoni: in vivo and in vitro evaluation

2018 ◽  
Vol 118 (1) ◽  
pp. 219-234 ◽  
Author(s):  
Hager S. Zoghroban ◽  
Samy I. El-Kowrany ◽  
Ibrahim A. Aboul Asaad ◽  
Gamal M. El Maghraby ◽  
Kholoud A. El-Nouby ◽  
...  
Keyword(s):  
Schistosoma Mansoni ◽  
In Vitro Evaluation ◽  
Enhanced Activity

Migration of T Cells in Vivo: Molecular Mechanisms and Clinical Implications

2001 ◽  
Vol 135 (4) ◽  
pp. 279 ◽  
Author(s):  
Jürgen Westermann ◽  
Britta Engelhardt ◽  
Jörg C. Hoffmann
Keyword(s):  
T Cells ◽  
Molecular Mechanisms ◽  
Clinical Implications

Dynamic organization of the mitochondrial protein import machinery

2016 ◽  
Vol 397 (11) ◽  
pp. 1097-1114 ◽  
Author(s):  
Sebastian P. Straub ◽  
Sebastian B. Stiller ◽  
Nils Wiedemann ◽  
Nikolaus Pfanner
Keyword(s):  
Mitochondrial Membrane ◽  
Protein Import ◽  
Mitochondrial Protein ◽  
Membrane Dynamics ◽  
Intermembrane Space ◽  
Mitochondrial Protein Import ◽  
Precursor Proteins ◽  
Dynamic Cooperation

Abstract Mitochondria contain elaborate machineries for the import of precursor proteins from the cytosol. The translocase of the outer mitochondrial membrane (TOM) performs the initial import of precursor proteins and transfers the precursors to downstream translocases, including the presequence translocase and the carrier translocase of the inner membrane, the mitochondrial import and assembly machinery of the intermembrane space, and the sorting and assembly machinery of the outer membrane. Although the protein translocases can function as separate entities in vitro, recent studies revealed a close and dynamic cooperation of the protein import machineries to facilitate efficient transfer of precursor proteins in vivo. In addition, protein translocases were found to transiently interact with distinct machineries that function in the respiratory chain or in the maintenance of mitochondrial membrane architecture. Mitochondrial protein import is embedded in a regulatory network that ensures protein biogenesis, membrane dynamics, bioenergetic activity and quality control.

PROBLEMS ASSOCIATED WITH THE USE OF THE EXPOSED PLATINUM ELECTRODE FOR MEASURING OXYGEN TENSION IN VIVO

1958 ◽  
Vol 36 (10) ◽  
pp. 1009-1021 ◽  
Author(s):  
William Rodger Inch
Keyword(s):  
Oxygen Tension ◽  
Oxygen Diffusion ◽  
Platinum Electrode ◽  
Diffusion Current ◽  
Protein Solutions ◽  
Buffer Solution ◽  
Electrode Current ◽  
Necessary And Sufficient

The equation governing the distribution of oxygen around a stationary exposed platinum electrode was solved for the size of electrode used and for a number of different times. In protein solutions the oxygen polarogram could be satisfactorily monitored by measuring the diffusion current at −0.6 and −0.7 volts. After using the platinum electrode in solutions containing protein it was found necessary and sufficient to clean it in acid dichromate solution followed by neutralization in a buffer solution. This procedure reproduced the original diffusion current. In solutions containing heterogeneities with small coefficients of oxygen diffusion, the electrode current was found to be less than when the heterogeneities were not present.

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