scholarly journals Structures of PKA-phospholamban complexes reveal a mechanism of familial dilated cardiomyopathy

2021 ◽  
Author(s):  
Juan Qin ◽  
Jingfeng Zhang ◽  
Lianyun Lin ◽  
Omid Haji-Ghassemi ◽  
Zhi Lin ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Calcium Uptake ◽  
Catalytic Domain ◽  
Common Disease ◽  
Wild Type ◽  
Disease Mechanism ◽  
Familial Dilated Cardiomyopathy ◽  
Phosphorylation Level ◽  
Biochemical Assays ◽  
Fight Or Flight Response

Several mutations identified in phospholamban (PLN) have been linked to familial dilated cardiomyopathy (DCM) and heart failure, yet the underlying molecular mechanism remains controversial. PLN interacts with sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) and regulates calcium uptake, which is modulated by the protein kinase A (PKA)-dependent phosphorylation of PLN during the fight-or-flight response. Here, we present the crystal structures of the catalytic domain of PKA in complex with wild-type and DCM-mutant PLNs. Our structures, combined with the results from other biophysical and biochemical assays, reveal a common disease mechanism: the mutations in PLN reduce its phosphorylation level by changing its conformation and weakening its interactions with PKA. In addition, we demonstrate that another more ubiquitous SERCA-regulatory peptide, called another-regulin (ALN), shares a similar mechanism mediated by PKA in regulating SERCA activity.

scholarly journals Structural, Dynamical, and Energetical Consequences of Rett Syndrome Mutation R133C in MeCP2

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Tugba G. Kucukkal ◽  
Emil Alexov
Keyword(s):  
Rett Syndrome ◽  
Experimental Studies ◽  
Common Disease ◽  
Salt Bridges ◽  
Wild Type ◽  
Disease Mechanism ◽  
Neurodevelopmental Disease ◽  
Mecp2 Protein ◽  
Dynamics Simulations ◽  
The Impact

Rett Syndrome (RTT) is a progressive neurodevelopmental disease affecting females. RTT is caused by mutations in theMECP2gene and various amino acid substitutions have been identified clinically in different domains of the multifunctional MeCP2 protein encoded by this gene. The R133C variant in the methylated-CpG-binding domain (MBD) of MeCP2 is the second most common disease-causing mutation in the MBD. Comparative molecular dynamics simulations of R133C mutant and wild-type MBD have been performed to understand the impact of the mutation on structure, dynamics, and interactions of the protein and subsequently understand the disease mechanism. Two salt bridges within the protein and two critical hydrogen bonds between the protein and DNA are lost upon the R133C mutation. The mutation was found to weaken the interaction with DNA and also cause loss of helicity within the 141-144 region. The structural, dynamical, and energetical consequences of R133C mutation were investigated in detail at the atomic resolution. Several important implications of this have been shown regarding protein stability and hydration dynamics as well as its interaction with DNA. The results are in agreement with previous experimental studies and further provide atomic level understanding of the molecular origin of RTT associated with R133C variant.

A case of familial dilated cardiomyopathy

2013 ◽  
Vol 34 (S 01) ◽  
Author(s):  
P Hutsteiner ◽  
N Jenewein ◽  
J Christ ◽  
O Ortmann ◽  
U Germer
Keyword(s):  
Dilated Cardiomyopathy ◽  
Familial Dilated Cardiomyopathy

Localization of a Gene Responsible for Familial Dilated Cardiomyopathy to Chromosome 1q32

Circulation ◽  
1995 ◽  
Vol 92 (12) ◽  
pp. 3387-3389 ◽  
Author(s):  
Jean-Bernard Durand ◽  
Linda L. Bachinski ◽  
Lisa C. Bieling ◽  
Grazyna Z. Czernuszewicz ◽  
Antoine B. Abchee ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Familial Dilated Cardiomyopathy

scholarly journals Reassessment of Gene-Elusive Familial Dilated Cardiomyopathy Leading to the Discovery of a Homozygous AARS2 Variant—The Importance of Regular Reassessment of Genetic Findings

2021 ◽  
Vol 11 (3) ◽  
pp. 122-128
Author(s):  
Priya Bhardwaj ◽  
Christoffer Rasmus Vissing ◽  
Niels Kjær Stampe ◽  
Kasper Rossing ◽  
Alex Hørby Christensen ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Genetic Screening ◽  
Sanger Sequencing ◽  
Mitochondrial Protein ◽  
Trna Synthetase ◽  
Familial Dilated Cardiomyopathy ◽  
Pathogenic Variants ◽  
Case Summary ◽  
Heterozygous Carriers ◽  
Important Enzyme

Background: AARS2 encodes the mitochondrial protein alanyl-tRNA synthetase 2 (MT-AlaRS), an important enzyme in oxidative phosphorylation. Variants in AARS2 have previously been associated with infantile cardiomyopathy. Case summary: A 4-year-old girl died of infantile-onset dilated cardiomyopathy (DCM) in 1996. Fifteen years later, her 21-year-old brother was diagnosed with DCM and ultimately underwent heart transplantation. Initial sequencing of 15 genes discovered no pathogenic variants in the brother at the time of his diagnosis. However, 9 years later re-screening in an updated screening panel of 129 genes identified a homozygous AARS2 (c.1774C > T) variant. Sanger sequencing of the deceased girl confirmed her to be homozygous for the AARS2 variant, while both parents and a third sibling were all found to be unaffected heterozygous carriers of the AARS2 variant. Discussion: This report underlines the importance of repeated and extended genetic screening of elusive families with suspected hereditary cardiomyopathies, as our knowledge of disease-causing mutations continuously grows. Although identification of the genetic etiology in the reported family would not have changed the clinical management, the genetic finding allows genetic counselling and holds substantial value in identifying at-risk relatives.

Review and Metaanalysis of the Frequency of Familial Dilated Cardiomyopathy

2011 ◽  
Vol 108 (8) ◽  
pp. 1171-1176 ◽  
Author(s):  
Mario Petretta ◽  
Flora Pirozzi ◽  
Laura Sasso ◽  
Antonella Paglia ◽  
Domenico Bonaduce
Keyword(s):  
Dilated Cardiomyopathy ◽  
Familial Dilated Cardiomyopathy

scholarly journals Subunit Interactions in the mariner Transposase

Genetics ◽  
1996 ◽  
Vol 144 (3) ◽  
pp. 1087-1095 ◽  
Author(s):  
Allan R Lohe ◽  
David T Sullivan ◽  
Daniel L Hartl
Keyword(s):  
Hybrid System ◽  
Catalytic Domain ◽  
Wild Type ◽  
Target Element ◽  
Yeast Two Hybrid ◽  
Subunit Interactions ◽  
Hsp70 Promoter ◽  
Yeast Two Hybrid System ◽  
Transposition Reaction ◽  
Two Hybrid

Abstract We have studied the Mos1 transposase encoded by the transposable element mariner. This transposase is a member of the “D,D(35)E” superfamily of proteins exhibiting the motif D,D(34)D. It is not known whether this transposase, or other eukaryote transposases manifesting the D,D(35)E domain, functions in a multimeric form. Evidence for oligomerization was found in the negative complementation of Mos1 by an EMS-induced transposase mutation in the catalytic domain. The transposase produced by this mutation has a glycine-to-arginine replacement at position 292. The G292R mutation strongly interferes with the ability of wild-type transposase to catalyze excision of a target element. Negative complementation was also observed for two other EMS mutations, although the effect was weaker than observed with G292R. Results from the yeast two-hybrid system also imply that Mos1 subunits interact, suggesting the possibility of subunit oligomerization in the transposition reaction. Overproduction of Mos1 subunits through an hsp70 promoter also inhibits excision of the target element, possibly through autoregulatory feedback on transcription or through formation of inactive or less active oligomers. The effects of both negative complementation and overproduction may contribute to the regulation of mariner transposition.

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