scholarly journals Pregnancy-Associated Plasma Protein (PAPP)-A2 in Physiology and Disease

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3576
Author(s):  
Vicente Barrios ◽  
Julie A. Chowen ◽  
Álvaro Martín-Rivada ◽  
Santiago Guerra-Cantera ◽  
Jesús Pozo ◽  
...  
Keyword(s):  
Plasma Protein ◽  
Human Growth ◽  
Gene Encoding ◽  
Growth Physiology ◽  
Precise Control ◽  
Specific Manner ◽  
Igf Receptor ◽  
Time Specific ◽  
Shed Light ◽  
New Mutations

The growth hormone (GH)/insulin-like growth factor (IGF) axis plays fundamental roles during development, maturation, and aging. Members of this axis, composed of various ligands, receptors, and binding proteins, are regulated in a tissue- and time-specific manner that requires precise control that is not completely understood. Some of the most recent advances in understanding the implications of this axis in human growth are derived from the identifications of new mutations in the gene encoding the pregnancy-associated plasma protein PAPP-A2 protease that liberates IGFs from their carrier proteins in a selective manner to allow binding to the IGF receptor 1. The identification of three nonrelated families with mutations in the PAPP-A2 gene has shed light on how this protease affects human physiology. This review summarizes our understanding of the implications of PAPP-A2 in growth physiology, obtained from studies in genetically modified animal models and the PAPP-A2 deficient patients known to date.

scholarly journals Reverse evolution leads to genotypic incompatibility despite functional and active site convergence

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Miriam Kaltenbach ◽  
Colin J Jackson ◽  
Eleanor C Campbell ◽  
Florian Hollfelder ◽  
Nobuhiko Tokuriki
Keyword(s):  
Active Site ◽  
Adaptive Landscape ◽  
Sequence Structure ◽  
Activity Increase ◽  
Enzyme Active Site ◽  
Fundamental Relationship ◽  
And Function ◽  
Alternative Set ◽  
Shed Light ◽  
New Mutations

Understanding the extent to which enzyme evolution is reversible can shed light on the fundamental relationship between protein sequence, structure, and function. Here, we perform an experimental test of evolutionary reversibility using directed evolution from a phosphotriesterase to an arylesterase, and back, and examine the underlying molecular basis. We find that wild-type phosphotriesterase function could be restored (>104-fold activity increase), but via an alternative set of mutations. The enzyme active site converged towards its original state, indicating evolutionary constraints imposed by catalytic requirements. We reveal that extensive epistasis prevents reversions and necessitates fixation of new mutations, leading to a functionally identical sequence. Many amino acid exchanges between the new and original enzyme are not tolerated, implying sequence incompatibility. Therefore, the evolution was phenotypically reversible but genotypically irreversible. Our study illustrates that the enzyme's adaptive landscape is highly rugged, and different functional sequences may constitute separate fitness peaks.

scholarly journals Plasma Protein Corona Modulates the Vascular Wall Interaction of Drug Carriers in a Material and Donor Specific Manner

PLoS ONE ◽  
2014 ◽  
Vol 9 (9) ◽  
pp. e107408 ◽  
Author(s):  
Daniel J. Sobczynski ◽  
Phapanin Charoenphol ◽  
Michael J. Heslinga ◽  
Peter J. Onyskiw ◽  
Katawut Namdee ◽  
...  
Keyword(s):  
Plasma Protein ◽  
Protein Corona ◽  
Drug Carriers ◽  
Vascular Wall ◽  
Specific Manner ◽  
Wall Interaction

scholarly journals Tissue-specific, developmental, hormonal, and dietary regulation of rat phosphoenolpyruvate carboxykinase-human growth hormone fusion genes in transgenic mice.

1992 ◽  
Vol 12 (3) ◽  
pp. 1007-1020 ◽  
Author(s):  
M K Short ◽  
D E Clouthier ◽  
I M Schaefer ◽  
R E Hammer ◽  
M A Magnuson ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Transgenic Mice ◽  
Human Growth Hormone ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Human Growth ◽  
Fusion Genes ◽  
Specific Expression ◽  
Tissue Specific ◽  
Cis Acting ◽  
Specific Manner

The cytosolic phosphoenolpyruvate carboxykinase (PEPCK) gene is expressed in multiple tissues and is regulated in a complex tissue-specific manner. To map the cis-acting DNA elements that direct this tissue-specific expression, we made transgenic mice containing truncated PEPCK-human growth hormone (hGH) fusion genes. The transgenes contained PEPCK promoter fragments with 5' endpoints at -2088, -888, -600, -402, and -207 bp, while the 3' endpoint was at +69 bp. Immunohistochemical analysis showed that the -2088 transgene was expressed in the correct cell types (hepatocytes, proximal tubular epithelium of the kidney, villar epithelium of the small intestine, epithelium of the colon, smooth muscle of the vagina and lungs, ductal epithelium of the sublingual gland, and white and brown adipocytes). Solution hybridization of hGH mRNA expressed from the transgenes indicated that white and brown fat-specific elements are located distally (-2088 to -888 bp) and that liver-, gut-, and kidney-specific elements are located proximally (-600 to +69 bp). However, elements outside of the region tested are necessary for the correct developmental pattern and level of PEPCK expression in kidney. Both the -2088 and -402 transgenes responded in a tissue-specific manner to dietary stimuli, and the -2088 transgene responded to glucocorticoid stimuli. Thus, different tissues utilize distinct cell-specific cis-acting elements to direct and regulate the PEPCK gene.

scholarly journals Subcellular Localization of Fad1p in Saccharomyces cerevisiae: A Choice at Post-Transcriptional Level?

Life ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 967 ◽  
Author(s):  
Francesco Bruni ◽  
Teresa Anna Giancaspero ◽  
Mislav Oreb ◽  
Maria Tolomeo ◽  
Piero Leone ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Protein Targeting ◽  
Bioinformatic Analysis ◽  
Protein Product ◽  
Transcriptional Level ◽  
Mitochondrial Localization ◽  
Gene Encoding ◽  
Cis Acting ◽  
Per Se ◽  
Shed Light

FAD synthase is the last enzyme in the pathway that converts riboflavin into FAD. In Saccharomyces cerevisiae, the gene encoding for FAD synthase is FAD1, from which a sole protein product (Fad1p) is expected to be generated. In this work, we showed that a natural Fad1p exists in yeast mitochondria and that, in its recombinant form, the protein is able, per se, to both enter mitochondria and to be destined to cytosol. Thus, we propose that FAD1 generates two echoforms—that is, two identical proteins addressed to different subcellular compartments. To shed light on the mechanism underlying the subcellular destination of Fad1p, the 3′ region of FAD1 mRNA was analyzed by 3′RACE experiments, which revealed the existence of (at least) two FAD1 transcripts with different 3′UTRs, the short one being 128 bp and the long one being 759 bp. Bioinformatic analysis on these 3′UTRs allowed us to predict the existence of a cis-acting mitochondrial localization motif, present in both the transcripts and, presumably, involved in protein targeting based on the 3′UTR context. Here, we propose that the long FAD1 transcript might be responsible for the generation of mitochondrial Fad1p echoform.

scholarly journals Single-copy chromosomal integration systems for Francisella tularensis

Microbiology ◽  
2009 ◽  
Vol 155 (4) ◽  
pp. 1152-1163 ◽  
Author(s):  
Eric D. LoVullo ◽  
Claudia R. Molins-Schneekloth ◽  
Herbert P. Schweizer ◽  
Martin S. Pavelka
Keyword(s):  
Francisella Tularensis ◽  
High Frequency ◽  
Genetic Manipulation ◽  
Single Copy ◽  
Gene Encoding ◽  
Highly Pathogenic ◽  
Pathogenic Organism ◽  
Allelic Exchange ◽  
Specific Manner ◽  
A Site

Francisella tularensis is a fastidious Gram-negative bacterium responsible for the zoonotic disease tularemia. Investigation of the biology and molecular pathogenesis of F. tularensis has been limited by the difficulties in manipulating such a highly pathogenic organism and by a lack of genetic tools. However, recent advances have substantially improved the ability of researchers to genetically manipulate this organism. To expand the molecular toolbox we have developed two systems to stably integrate genetic elements in single-copy into the F. tularensis genome. The first system is based upon the ability of transposon Tn7 to insert in both a site- and orientation-specific manner at high frequency into the attTn7 site located downstream of the highly conserved glmS gene. The second system consists of a sacB-based suicide plasmid used for allelic exchange of unmarked elements with the blaB gene, encoding a β-lactamase, resulting in the replacement of blaB with the element and the loss of ampicillin resistance. To test these new tools we used them to complement a novel d-glutamate auxotroph of F. tularensis LVS, created using an improved sacB-based allelic exchange plasmid. These new systems will be helpful for the genetic manipulation of F. tularensis in studies of tularemia biology, especially where the use of multi-copy plasmids or antibiotic markers may not be suitable.

Increased or Decreased Levels of Caenorhabditis elegans lon-3, a Gene Encoding a Collagen, Cause Reciprocal Changes in Body Length

Genetics ◽  
2002 ◽  
Vol 161 (1) ◽  
pp. 83-97 ◽  
Author(s):  
Josefin Nyström ◽  
Zai-Zhong Shen ◽  
Margareta Aili ◽  
Anthony J Flemming ◽  
Armand Leroi ◽  
...  
Keyword(s):  
Body Length ◽  
Gene Copy Number ◽  
Gene Copy ◽  
Loss Of Function ◽  
Gene Encoding ◽  
C Elegans ◽  
Morphometric Analyses ◽  
Genes Encoding ◽  
New Mutations

Abstract Body length in C. elegans is regulated by a member of the TGFβ family, DBL-1. Loss-of-function mutations in dbl-1, or in genes encoding components of the signaling pathway it activates, cause worms to be shorter than wild type and slightly thinner (Sma). Overexpression of dbl-1 confers the Lon phenotype characterized by an increase in body length. We show here that loss-of-function mutations in dbl-1 and lon-1, respectively, cause a decrease or increase in the ploidy of nuclei in the hypodermal syncytial cell, hyp7. To learn more about the regulation of body length in C. elegans we carried out a genetic screen for new mutations causing a Lon phenotype. We report here the cloning and characterization of lon-3. lon-3 is shown to encode a putative cuticle collagen that is expressed in hypodermal cells. We show that, whereas putative null mutations in lon-3 (or reduction of lon-3 activity by RNAi) causes a Lon phenotype, increasing lon-3 gene copy number causes a marked reduction in body length. Morphometric analyses indicate that the lon-3 loss-of-function phenotype resembles that caused by overexpression of dbl-1. Furthermore, phenotypes caused by defects in dbl-1 or lon-3 expression are in both cases suppressed by a null mutation in sqt-1, a second cuticle collagen gene. However, whereas loss of dbl-1 activity causes a reduction in hypodermal endoreduplication, the reduction in body length associated with overexpression of lon-3 occurs in the absence of defects in hypodermal ploidy.

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