Comprehensive, human cellular protein databases and their implication for the study of genome organization and function

The Akt family of serine-threonine kinases participates in diverse cellular processes, including the promotion of cell survival, glucose metabolism, and cellular protein synthesis. All three known Akt family members, Akt1, Akt2 and Akt3, are expressed in the myocardium, although Akt1 and Akt2 are most abundant. Previous studies demonstrated that Akt1 and Akt3 overexpression results in enhanced myocardial size and function. Yet, little is known about the role of Akt2 in modulating cardiac metabolism, survival, and growth. Here, we utilize murine models with targeted disruption of the akt2 or the akt1 genes to demonstrate that Akt2, but not Akt1, is required for insulin-stimulated 2-[3H]deoxyglucose uptake and metabolism. In contrast, akt2-/- mice displayed normal cardiac growth responses to provocative stimulation, including ligand stimulation of cultured cardiomyocytes, pressure overload by transverse aortic constriction, and myocardial infarction. However, akt2-/- mice were found to be sensitized to cardiomyocyte apoptosis in response to ischemic injury, and apoptosis was significantly increased in the peri-infarct zone of akt2-/- hearts 7 days after occlusion of the left coronary artery. These results implicate Akt2 in the regulation of cardiomyocyte metabolism and survival.

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Abstract 85: The AAA-ATPase p97 is a Critical Regulator of Cardiac Homeostasis

Circulation Research ◽

10.1161/res.121.suppl_1.85 ◽

2017 ◽

Vol 121 (suppl_1) ◽

Author(s):

Matthew J Brody ◽

Michelle A Sargent ◽

Jeffery D Molkentin

Keyword(s):

Quality Control ◽

Protein Quality ◽

Protein Complexes ◽

Protein Quality Control ◽

Ubiquitin Proteasome System ◽

Cellular Protein ◽

Dominant Negative ◽

Aaa Atpase ◽

And Function ◽

Thrombospondin 4

p97 is a AAA-ATPase that plays critical roles in a myriad of cellular protein quality control processes, including the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway that targets misfolded proteins in the ER for degradation in the cytosol by the ubiquitin proteasome system. Mutations in p97 cause a multisystem degenerative proteinopathy disorder called inclusion body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD) that includes pathologies of the nervous system, skeletal muscle, bone, and heart. Previous studies in the laboratory into the mechanisms whereby thrombospondin 4 has its cardioprotective effects and enhanced ERAD activity identified p97 as a direct interacting partner. This observation suggested that p97 itself could be an important cardioprotective effector by benefiting protein quality control in the heart. To address this hypothesis here we generated cardiac-specific transgenic mice overexpressing wildtype p97 or a p97 K524A mutant with deficient ATPase activity, the latter of which functioned as a dominant negative. Mice overexpressing wildtype p97 exhibit normal cardiac structure and function while mutant p97 overexpressing mice develop cardiomyopathy, upregulate several ERAD complex components, and have elevated levels of ubiquitinated proteins. Proteomics and immunoprecipitation assays identified overwhelming interactions between endogenous p97 and a number of interesting protein complexes that suggest unique functions for this protein in regulating protein quality control in the heart. The results and novel regulatory relationships will be presented, which suggests entirely unique pathways whereby p97 functions in the heart.

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Technologies to study spatial genome organization: beyond 3C

Briefings in Functional Genomics ◽

10.1093/bfgp/elz019 ◽

2019 ◽

Author(s):

Nadine Übelmesser ◽

Argyris Papantonis

Keyword(s):

Genome Organization ◽

Nuclear Organization ◽

Three Dimensional ◽

Nuclear Space ◽

Chromosome Conformation ◽

Novel Variants ◽

Cell Processes ◽

Systematic Biases ◽

And Function ◽

Spatial Genome Organization

Abstract The way that chromatin is organized in three-dimensional nuclear space is now acknowledged as a factor critical for the major cell processes, like transcription, replication and cell division. Researchers have been armed with new molecular and imaging technologies to study this structure-to-function link of genomes, spearheaded by the introduction of the ‘chromosome conformation capture’ technology more than a decade ago. However, this technology is not without shortcomings, and novel variants and orthogonal approaches are being developed to overcome these. As a result, the field of nuclear organization is constantly fueled by methods of increasing resolution and/or throughput that strive to eliminate systematic biases and increase precision. In this review, we attempt to highlight the most recent advances in technology that promise to provide novel insights on how chromosomes fold and function.

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Genome organization at different scales: nature, formation and function

Current Opinion in Cell Biology ◽

10.1016/j.ceb.2018.03.009 ◽

2018 ◽

Vol 52 ◽

pp. 145-153 ◽

Cited By ~ 14

Author(s):

Jacques Serizay ◽

Julie Ahringer

Keyword(s):

Genome Organization ◽

And Function

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Chaperones and Proteostasis: Role in Parkinson’s Disease

Diseases ◽

10.3390/diseases8020024 ◽

2020 ◽

Vol 8 (2) ◽

pp. 24 ◽

Cited By ~ 1

Author(s):

Neha Joshi ◽

Atchaya Raveendran ◽

Shirisha Nagotu

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Three Dimensional ◽

Cellular Protein ◽

The Body ◽

Dimensional Structure ◽

Protein Homeostasis ◽

Altered Expression ◽

And Function ◽

Related Proteins

Proper folding to attain a defined three-dimensional structure is a prerequisite for the functionality of a protein. Improper folding that eventually leads to formation of protein aggregates is a hallmark of several neurodegenerative disorders. Loss of protein homeostasis triggered by cellular stress conditions is a major contributing factor for the formation of these toxic aggregates. A conserved class of proteins called chaperones and co-chaperones is implicated in maintaining the cellular protein homeostasis. Expanding the body of evidence highlights the role of chaperones as central mediators in the formation, de-aggregation and degradation of the aggregates. Altered expression and function of chaperones is associated with many neurodegenerative diseases including Parkinson’s disease. Several studies indicate that chaperones are at the center of the cause and effect cycle of this disease. An overview of the various chaperones that are associated with homeostasis of Parkinson’s disease-related proteins and their role in pathogenicity will be discussed in this review.

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The Spectrinome: The Interactome of a Scaffold Protein Creating Nuclear and Cytoplasmic Connectivity and Function

Experimental Biology and Medicine ◽

10.1177/1535370219867269 ◽

2019 ◽

Vol 244 (15) ◽

pp. 1273-1302 ◽

Cited By ~ 3

Author(s):

Steven R. Goodman ◽

Daniel Johnson ◽

Steven L. Youngentob ◽

David Kakhniashvili

Keyword(s):

Cell Surface ◽

Intracellular Signaling ◽

Cellular Protein ◽

Human Diseases ◽

Scaffolding Protein ◽

Eukaryotic Cells ◽

Cellular Functions ◽

Cellular Compartment ◽

Atlas Data ◽

And Function

We provide a review of Spectrin isoform function in the cytoplasm, the nucleus, the cell surface, and in intracellular signaling. We then discuss the importance of Spectrin’s E2/E3 chimeric ubiquitin conjugating and ligating activity in maintaining cellular homeostasis. Finally we present spectrin isoform subunit specific human diseases. We have created the Spectrinome, from the Human Proteome, Human Reactome and Human Atlas data and demonstrated how it can be a useful tool in visualizing and understanding spectrins myriad of cellular functions. Impact statement Spectrin was for the first 12 years after its discovery thought to be found only in erythrocytes. In 1981, Goodman and colleagues 1 found that spectrin-like molecules were ubiquitously found in non-erythroid cells leading to a great multitude of publications over the next thirty eight years. The discovery of multiple spectrin isoforms found associated with every cellular compartment, and representing 2-3% of cellular protein, has brought us to today’s understanding that spectrin is a scaffolding protein, with its own E2/E3 chimeric ubiquitin conjugating ligating activity that is involved in virtually every cellular function. We cover the history, localized functions of spectrin isoforms, human diseases caused by mutations, and provide the spectrinome: a useful tool for understanding the myriad of functions for one of the most important proteins in all eukaryotic cells.

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