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Article: Transcriptome data analysis of primary cardiomyopathies reveals perturbations in arachidonic acid metabolism.

Chauhan, Pankaj Kumar / Sowdhamini, Ramanathan

2023 Volume 10, Page(s) 1110119

Abstract: Introduction: Cardiomyopathies are complex heart diseases with significant prevalence around the world. Among these, primary forms are the major contributors to heart failure and sudden cardiac death. As a high-energy demanding engine, the heart ... ...

Abstract	Introduction: Cardiomyopathies are complex heart diseases with significant prevalence around the world. Among these, primary forms are the major contributors to heart failure and sudden cardiac death. As a high-energy demanding engine, the heart utilizes fatty acids, glucose, amino acid, lactate and ketone bodies for energy to meet its requirement. However, continuous myocardial stress and cardiomyopathies drive towards metabolic impairment that advances heart failure (HF) pathogenesis. So far, metabolic profile correlation across different cardiomyopathies remains poorly understood. Methods: In this study, we systematically explore metabolic differences amongst primary cardiomyopathies. By assessing the metabolic gene expression of all primary cardiomyopathies, we highlight the significantly shared and distinct metabolic pathways that may represent specialized adaptations to unique cellular demands. We utilized publicly available RNA-seq datasets to profile global changes in the above diseases (\| Results: Our analysis demonstrates that genes in arachidonic acid metabolism (AA) are significantly perturbed across cardiomyopathies. In particular, the arachidonic acid metabolism gene Conclusion: The profound significance of AA metabolism within the cardiovascular system renders it a key player in modulating the phenotypes of cardiomyopathies.
Language	English
Publishing date	2023-05-23
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2781496-8
ISSN	2297-055X
ISSN	2297-055X
DOI	10.3389/fcvm.2023.1110119
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Article ; Online: LIM domain-wide comprehensive virtual mutagenesis provides structural rationale for cardiomyopathy mutations in CSRP3

Pankaj Kumar Chauhan / Sowdhamini Ramanathan

Scientific Reports, Vol 12, Iss 1, Pp 1-

2022 Volume 11

Abstract: Abstract Cardiomyopathies are a severe and chronic cardiovascular burden worldwide, affecting a large cohort in the general population. Cysteine and glycine-rich protein 3 (CSRP3) is one of key proteins implicated in dominant dilated cardiomyopathy (DCM) ...

Abstract	Abstract Cardiomyopathies are a severe and chronic cardiovascular burden worldwide, affecting a large cohort in the general population. Cysteine and glycine-rich protein 3 (CSRP3) is one of key proteins implicated in dominant dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). In this study, we device a rapid in silico screening protocol that creates a mutational landscape map for all possible allowed and disallowed substitutions in the protein of interest. This map provides the structural and functional insights on the stability of LIM domains of CSRP3. Further, the sequence analysis delineates the eukaryotic CSRP3 protein orthologs which complements the mutational map, but provide limited information of amino acid exchanges. Next, we also evaluated the effect of HCM/DCM mutations on these domains. One of highly destabilising mutations—L44P (also disease causing) and a neutral mutation—L44M were further subjected to molecular dynamics (MD) simulations. The results establish that L44P substitution affects the LIM domain structure by altering secondary structure and due to loss of hydrophobic interaction with Phenylananine 35. The present study provides a useful perspective to our understanding of the role of mutations in the CSRP3 LIM domains and their evolution. This study provides a novel computational screening method for quick identification of key mutation sites for specific protein structures that can reduce the burden on experimental research.
Keywords	Medicine ; R ; Science ; Q
Subject code	612
Language	English
Publishing date	2022-03-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Integrative network analysis interweaves the missing links in cardiomyopathy diseasome.

Chauhan, Pankaj Kumar / Sowdhamini, Ramanathan

Scientific reports

2022 Volume 12, Issue 1, Page(s) 19670

Abstract: Cardiomyopathies are progressive disease conditions that give rise to an abnormal heart phenotype and are a leading cause of heart failures in the general population. These are complex diseases that show co-morbidity with other diseases. The molecular ... ...

Abstract	Cardiomyopathies are progressive disease conditions that give rise to an abnormal heart phenotype and are a leading cause of heart failures in the general population. These are complex diseases that show co-morbidity with other diseases. The molecular interaction network in the localised disease neighbourhood is an important step toward deciphering molecular mechanisms underlying these complex conditions. In this pursuit, we employed network medicine techniques to systematically investigate cardiomyopathy's genetic interplay with other diseases and uncover the molecular players underlying these associations. We predicted a set of candidate genes in cardiomyopathy by exploring the DIAMOnD algorithm on the human interactome. We next revealed how these candidate genes form association across different diseases and highlighted the predominant association with brain, cancer and metabolic diseases. Through integrative systems analysis of molecular pathways, heart-specific mouse knockout data and disease tissue-specific transcriptomic data, we screened and ascertained prominent candidates that show abnormal heart phenotype, including NOS3, MMP2 and SIRT1. Our computational analysis broadens the understanding of the genetic associations of cardiomyopathies with other diseases and holds great potential in cardiomyopathy research.
MeSH term(s)	Humans ; Mice ; Animals ; Cardiomyopathies/genetics ; Phenotype ; Algorithms ; Heart
Language	English
Publishing date	2022-11-16
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-022-24246-x
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Article ; Online: Computational analysis of potential candidate genes involved in the cold stress response of ten Rosaceae members.

Shafi, K Mohamed / Sowdhamini, Ramanathan

BMC genomics

2022 Volume 23, Issue 1, Page(s) 516

Abstract: Background: Plant species from Rosaceae family are economically important. One of the major environmental factors impacting those species is cold stress. Although several Rosaceae plant genomes have recently been sequenced, there have been very few ... ...

Abstract	Background: Plant species from Rosaceae family are economically important. One of the major environmental factors impacting those species is cold stress. Although several Rosaceae plant genomes have recently been sequenced, there have been very few research conducted on cold upregulated genes and their promoter binding sites. In this study, we used computational approaches to identify and analyse potential cold stress response genes across ten Rosaceae family members. Results: Cold stress upregulated gene data from apple and strawberry were used to identify syntelogs in other Rosaceae species. Gene duplication analysis was carried out to better understand the distribution of these syntelog genes in different Rosaceae members. A total of 11,145 popular abiotic stress transcription factor-binding sites were identified in the upstream region of these potential cold-responsive genes, which were subsequently categorised into distinct transcription factor (TF) classes. MYB classes of transcription factor binding site (TFBS) were abundant, followed by bHLH, WRKY, and AP2/ERF. TFBS patterns in the promoter regions were compared among these species and gene families, found to be quite different even amongst functionally related syntelogs. A case study on important cold stress responsive transcription factor family, AP2/ERF showed less conservation in TFBS patterns in the promoter regions. This indicates that syntelogs from the same group may be comparable at the gene level but not at the level of cis-regulatory elements. Therefore, for such genes from the same family, different repertoire of TFs could be recruited for regulation and expression. Duplication events must have played a significant role in the similarity of TFBS patterns amongst few syntelogs of closely related species. Conclusions: Our study overall suggests that, despite being from the same gene family, different combinations of TFs may play a role in their regulation and expression. The findings of this study will provide information about potential genes involved in the cold stress response, which will aid future functional research of these gene families involved in many important biological processes.
MeSH term(s)	Cold-Shock Response/genetics ; Gene Expression Regulation, Plant ; Multigene Family ; Phylogeny ; Plant Proteins/genetics ; Plant Proteins/metabolism ; Rosaceae/genetics ; Rosaceae/metabolism ; Stress, Physiological/genetics ; Transcription Factors/genetics ; Transcription Factors/metabolism
Chemical Substances	Plant Proteins ; Transcription Factors
Language	English
Publishing date	2022-07-16
Publishing country	England
Document type	Journal Article
ZDB-ID	2041499-7
ISSN	1471-2164 ; 1471-2164
ISSN (online)	1471-2164
ISSN	1471-2164
DOI	10.1186/s12864-022-08751-x
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Article ; Online: LIM domain-wide comprehensive virtual mutagenesis provides structural rationale for cardiomyopathy mutations in CSRP3.

Chauhan, Pankaj Kumar / Sowdhamini, Ramanathan

Scientific reports

2022 Volume 12, Issue 1, Page(s) 3562

Abstract: Cardiomyopathies are a severe and chronic cardiovascular burden worldwide, affecting a large cohort in the general population. Cysteine and glycine-rich protein 3 (CSRP3) is one of key proteins implicated in dominant dilated cardiomyopathy (DCM) and ... ...

Abstract	Cardiomyopathies are a severe and chronic cardiovascular burden worldwide, affecting a large cohort in the general population. Cysteine and glycine-rich protein 3 (CSRP3) is one of key proteins implicated in dominant dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). In this study, we device a rapid in silico screening protocol that creates a mutational landscape map for all possible allowed and disallowed substitutions in the protein of interest. This map provides the structural and functional insights on the stability of LIM domains of CSRP3. Further, the sequence analysis delineates the eukaryotic CSRP3 protein orthologs which complements the mutational map, but provide limited information of amino acid exchanges. Next, we also evaluated the effect of HCM/DCM mutations on these domains. One of highly destabilising mutations-L44P (also disease causing) and a neutral mutation-L44M were further subjected to molecular dynamics (MD) simulations. The results establish that L44P substitution affects the LIM domain structure by altering secondary structure and due to loss of hydrophobic interaction with Phenylananine 35. The present study provides a useful perspective to our understanding of the role of mutations in the CSRP3 LIM domains and their evolution. This study provides a novel computational screening method for quick identification of key mutation sites for specific protein structures that can reduce the burden on experimental research.
MeSH term(s)	Cardiomyopathy, Hypertrophic/genetics ; Cardiomyopathy, Hypertrophic/metabolism ; Humans ; LIM Domain Proteins/genetics ; Muscle Proteins/metabolism ; Mutagenesis ; Mutation
Chemical Substances	LIM Domain Proteins ; Muscle Proteins
Language	English
Publishing date	2022-03-03
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-022-07553-1
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Article ; Online: A genome-wide search of Toll/Interleukin-1 receptor (TIR) domain-containing adapter molecule (TICAM) and their evolutionary divergence from other TIR domain containing proteins.

Verma, Shailya / Sowdhamini, Ramanathan

Biology direct

2022 Volume 17, Issue 1, Page(s) 24

Abstract: Toll/Interleukin-1 receptor (TIR) domains are cytoplasmic domain that mediates receptor signalling. These domains are present in proteins like Toll-like receptors (TLR), its signaling adaptors and Interleukins, that form a major part of the immune system. ...

Abstract	Toll/Interleukin-1 receptor (TIR) domains are cytoplasmic domain that mediates receptor signalling. These domains are present in proteins like Toll-like receptors (TLR), its signaling adaptors and Interleukins, that form a major part of the immune system. These TIR domain containing signaling adaptors binds to the TLRs and interacts with their TIR domains for downstream signaling. We have examined the evolutionary divergence across the tree of life of two of these TIR domain containing adaptor molecules (TICAM) i.e., TIR domain-containing adapter-inducing interferon-β (TRIF/TICAM1) and TIR domain containing adaptor molecule2 (TRAM/TICAM2), by using computational approaches. We studied their orthologs, domain architecture, conserved motifs, and amino acid variations. Our study also adds a timeframe to infer the duplication of TICAM protein from Leptocardii and later divergence into TICAM1/TRIF and TICAM2/TRAM. More evidence of TRIF proteins was seen, but the absence of conserved co-existing domains such as TRIF-NTD, TIR, and RHIM domains in distant relatives hints on diversification and adaptation to different biological functions. TRAM was lost in Actinopteri and has conserved domain architecture of TIR across species except in Aves. An additional isoform of TRAM, TAG (TRAM adaptor with the GOLD domain), could be identified in species in the Mesozoic era. Finally, the Hypothesis based Likelihood ratio test was applied to look for selection pressure amongst orthologues of TRIF and TRAM to search for positively selected sites. These residues were mostly seen in the non-structural region of the proteins. Overall, this study unravels evolutionary information on the adaptors TRAM and TRIF and how well they had duplicated to perform diverse functions by changes in their domain architecture across lineages.
MeSH term(s)	Adaptor Proteins, Vesicular Transport/chemistry ; Adaptor Proteins, Vesicular Transport/genetics ; Receptors, Interleukin-1/genetics ; Signal Transduction ; Toll-Like Receptors/genetics ; Toll-Like Receptors/metabolism
Chemical Substances	Adaptor Proteins, Vesicular Transport ; Receptors, Interleukin-1 ; Toll-Like Receptors
Language	English
Publishing date	2022-09-02
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2221028-3
ISSN	1745-6150 ; 1745-6150
ISSN (online)	1745-6150
ISSN	1745-6150
DOI	10.1186/s13062-022-00335-9
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Article ; Online: Author Correction: LIM domain-wide comprehensive virtual mutagenesis provides structural rationale for cardiomyopathy mutations in CSRP3.

Chauhan, Pankaj Kumar / Sowdhamini, Ramanathan

Scientific reports

2022 Volume 12, Issue 1, Page(s) 4363

Language	English
Publishing date	2022-03-14
Publishing country	England
Document type	Published Erratum
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-022-08526-0
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Article ; Online: Bioinformatics Analysis of Mutations Sheds Light on the Evolution of Dengue NS1 Protein With Implications in the Identification of Potential Functional and Druggable Sites.

Sharma, Abhishek / Krishna, Sudhir / Sowdhamini, Ramanathan

Molecular biology and evolution

2023 Volume 40, Issue 3

Abstract: Non-structural protein (NS1) is a 350 amino acid long conserved protein in the dengue virus. Conservation of NS1 is expected due to its importance in dengue pathogenesis. The protein is known to exist in dimeric and hexameric states. The dimeric state is ...

Abstract	Non-structural protein (NS1) is a 350 amino acid long conserved protein in the dengue virus. Conservation of NS1 is expected due to its importance in dengue pathogenesis. The protein is known to exist in dimeric and hexameric states. The dimeric state is involved in its interaction with host proteins and viral replication, and the hexameric state is involved in viral invasion. In this work, we performed extensive structure and sequence analysis of NS1 protein, and uncovered the role of NS1 quaternary states in its evolution. A three-dimensional modeling of unresolved loop regions in NS1 structure is performed. "Conserved" and "Variable" regions within NS1 protein were identified from sequences obtained from patient samples and the role of compensatory mutations in selecting destabilizing mutations were identified. Molecular dynamics (MD) simulations were performed to extensively study the effect of a few mutations on NS1 structure stability and compensatory mutations. Virtual saturation mutagenesis, predicting the effect of every individual amino acid substitution on NS1 stability sequentially, revealed virtual-conserved and variable sites. The increase in number of observed and virtual-conserved regions across NS1 quaternary states suggest the role of higher order structure formation in its evolutionary conservation. Our sequence and structure analysis could enable in identifying possible protein-protein interfaces and druggable sites. Virtual screening of nearly 10,000 small molecules, including FDA-approved drugs, permitted us to recognize six drug-like molecules targeting the dimeric sites. These molecules could be promising due to their stable interactions with NS1 throughout the simulation.
MeSH term(s)	Mutation ; Dengue ; Computational Biology ; Viral Nonstructural Proteins/genetics
Chemical Substances	Viral Nonstructural Proteins
Language	English
Publishing date	2023-02-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	998579-7
ISSN	1537-1719 ; 0737-4038
ISSN (online)	1537-1719
ISSN	0737-4038
DOI	10.1093/molbev/msad033
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Article ; Online: Interfacial residues in protein-protein complexes are in the eyes of the beholder.

Parvathy, Jayadevan / Yazhini, Arangasamy / Srinivasan, Narayanaswamy / Sowdhamini, Ramanathan

Proteins

2023 Volume 92, Issue 4, Page(s) 509–528

Abstract: Interactions between proteins are vital in almost all biological processes. The characterization of protein-protein interactions helps us understand the mechanistic basis of biological processes, thereby enabling the manipulation of proteins for ... ...

Abstract	Interactions between proteins are vital in almost all biological processes. The characterization of protein-protein interactions helps us understand the mechanistic basis of biological processes, thereby enabling the manipulation of proteins for biotechnological and clinical purposes. The interface residues of a protein-protein complex are assumed to have the following two properties: (a) they always interact with a residue of a partner protein, which forms the basis for distance-based interface residue identification methods, and (b) they are solvent-exposed in the isolated form of the protein and become buried in the complex form, which forms the basis for Accessible Surface Area (ASA)-based methods. The study interrogates this popular assumption by recognizing interface residues in protein-protein complexes through these two methods. The results show that a few residues are identified uniquely by each method, and the extent of conservation, propensities, and their contribution to the stability of protein-protein interaction varies substantially between these residues. The case study analyses showed that interface residues, unique to distance, participate in crucial interactions that hold the proteins together, whereas the interface residues unique to the ASA method have a potential role in the recognition, dynamics, and specificity of the complex and can also be a hotspot. Overall, the study recommends applying both distance and ASA methods so that some interface residues missed by either method but crucial to the stability, recognition, dynamics, and function of protein-protein complexes are identified in a complementary manner.
MeSH term(s)	Proteins/chemistry ; Solvents/chemistry ; Protein Binding
Chemical Substances	Proteins ; Solvents
Language	English
Publishing date	2023-11-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	806683-8
ISSN	1097-0134 ; 0887-3585
ISSN (online)	1097-0134
ISSN	0887-3585
DOI	10.1002/prot.26628
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Article ; Online: Comparative analysis of permanent and transient domain-domain interactions in multi-domain proteins.

Sidhanta, Swayam Prakash Das / Sowdhamini, Ramanathan / Srinivasan, Narayanaswamy

Proteins

2023

Abstract: Protein domains are structural, functional, and evolutionary units. These domains bring out the diversity of functionality by means of interactions with other co-existing domains and provide stability. Hence, it is important to study intra-protein inter- ... ...

Abstract	Protein domains are structural, functional, and evolutionary units. These domains bring out the diversity of functionality by means of interactions with other co-existing domains and provide stability. Hence, it is important to study intra-protein inter-domain interactions from the perspective of types of interactions. Domains within a chain could interact over short timeframes or permanently, rather like protein-protein interactions (PPIs). However, no systematic study has been carried out between two classes, namely permanent and transient domain-domain interactions. In this work, we studied 263 two-domain proteins, belonging to either of these classes and their interfaces on the basis of several factors, such as interface area and details of interactions (number, strength, and types of interactions). We also characterized them based on residue conservation at the interface, correlation of residue motions across domains, its involvement in repeat formation, and their involvement in particular molecular processes. Finally, we could analyze the interactions arising from domains in two-domain monomeric proteins, and we observed significant differences between these two classes of domain interactions and a few similarities. This study will help to obtain a better understanding of structure-function and folding principles of multi-domain proteins.
Language	English
Publishing date	2023-10-12
Publishing country	United States
Document type	Journal Article
ZDB-ID	806683-8
ISSN	1097-0134 ; 0887-3585
ISSN (online)	1097-0134
ISSN	0887-3585
DOI	10.1002/prot.26581
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