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Article ; Online: PON-SC - program for identifying steric clashes caused by amino acid substitutions.

Čalyševa, Jelena / Vihinen, Mauno

2017 Volume 18, Issue 1, Page(s) 531

Abstract: Background: Amino acid substitutions due to DNA nucleotide replacements are frequently disease-causing because of affecting functionally important sites. If the substituting amino acid does not fit into the protein, it causes structural alterations that ...

Abstract	Background: Amino acid substitutions due to DNA nucleotide replacements are frequently disease-causing because of affecting functionally important sites. If the substituting amino acid does not fit into the protein, it causes structural alterations that are often harmful. Clashes of amino acids cause local or global structural changes. Testing structural compatibility of variations has been difficult due to the lack of a dedicated method that could handle vast amounts of variation data produced by next generation sequencing technologies. Results: We developed a method, PON-SC, for detecting protein structural clashes due to amino acid substitutions. The method utilizes side chain rotamer library and tests whether any of the common rotamers can be fitted into the protein structure. The tool was tested both with variants that cause and do not cause clashes and found to have accuracy of 0.71 over five test datasets. Conclusions: We developed a fast method for residue side chain clash detection. The method provides in addition to the prediction also visualization of the variant in three dimensional structure.
MeSH term(s)	Algorithms ; Amino Acid Substitution ; Amino Acids/chemistry ; Amino Acids/metabolism ; Databases, Protein ; Protein Conformation ; Protein Engineering/methods ; Proteins/chemistry ; Proteins/genetics ; Proteins/metabolism ; Software
Chemical Substances	Amino Acids ; Proteins
Language	English
Publishing date	2017-11-29
Publishing country	England
Document type	Journal Article
ZDB-ID	2041484-5
ISSN	1471-2105 ; 1471-2105
ISSN (online)	1471-2105
ISSN	1471-2105
DOI	10.1186/s12859-017-1947-7
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Divergent Evolution of a Protein-Protein Interaction Revealed through Ancestral Sequence Reconstruction and Resurrection.

Laursen, Louise / Čalyševa, Jelena / Gibson, Toby J / Jemth, Per

Molecular biology and evolution

2020 Volume 38, Issue 1, Page(s) 152–167

Abstract: The postsynaptic density extends across the postsynaptic dendritic spine with discs large (DLG) as the most abundant scaffolding protein. DLG dynamically alters the structure of the postsynaptic density, thus controlling the function and distribution of ... ...

Abstract	The postsynaptic density extends across the postsynaptic dendritic spine with discs large (DLG) as the most abundant scaffolding protein. DLG dynamically alters the structure of the postsynaptic density, thus controlling the function and distribution of specific receptors at the synapse. DLG contains three PDZ domains and one important interaction governing postsynaptic architecture is that between the PDZ3 domain from DLG and a protein called cysteine-rich interactor of PDZ3 (CRIPT). However, little is known regarding functional evolution of the PDZ3:CRIPT interaction. Here, we subjected PDZ3 and CRIPT to ancestral sequence reconstruction, resurrection, and biophysical experiments. We show that the PDZ3:CRIPT interaction is an ancient interaction, which was likely present in the last common ancestor of Eukaryotes, and that high affinity is maintained in most extant animal phyla. However, affinity is low in nematodes and insects, raising questions about the physiological function of the interaction in species from these animal groups. Our findings demonstrate how an apparently established protein-protein interaction involved in cellular scaffolding in bilaterians can suddenly be subject to dynamic evolution including possible loss of function.
MeSH term(s)	Adaptor Proteins, Signal Transducing/metabolism ; Amino Acid Sequence ; Animals ; Cell Adhesion Molecules, Neuronal/chemistry ; DNA Mutational Analysis ; Evolution, Molecular ; Humans ; Loa/genetics ; Multigene Family ; PDZ Domains
Chemical Substances	Adaptor Proteins, Signal Transducing ; CRIPT protein, human ; Cell Adhesion Molecules, Neuronal ; neuroligin 1
Language	English
Publishing date	2020-08-04
Publishing country	United States
Document type	Comparative Study ; 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/msaa198
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Article ; Online: Short linear motif candidates in the cell entry system used by SARS-CoV-2 and their potential therapeutic implications.

Mészáros, Bálint / Sámano-Sánchez, Hugo / Alvarado-Valverde, Jesús / Čalyševa, Jelena / Martínez-Pérez, Elizabeth / Alves, Renato / Shields, Denis C / Kumar, Manjeet / Rippmann, Friedrich / Chemes, Lucía B / Gibson, Toby J

Science signaling

2021 Volume 14, Issue 665

Abstract: The first reported receptor for SARS-CoV-2 on host cells was the angiotensin-converting enzyme 2 (ACE2). However, the viral spike protein also has an RGD motif, suggesting that cell surface integrins may be co-receptors. We examined the sequences of ACE2 ...

Abstract	The first reported receptor for SARS-CoV-2 on host cells was the angiotensin-converting enzyme 2 (ACE2). However, the viral spike protein also has an RGD motif, suggesting that cell surface integrins may be co-receptors. We examined the sequences of ACE2 and integrins with the Eukaryotic Linear Motif (ELM) resource and identified candidate short linear motifs (SLiMs) in their short, unstructured, cytosolic tails with potential roles in endocytosis, membrane dynamics, autophagy, cytoskeleton, and cell signaling. These SLiM candidates are highly conserved in vertebrates and may interact with the μ2 subunit of the endocytosis-associated AP2 adaptor complex, as well as with various protein domains (namely, I-BAR, LC3, PDZ, PTB, and SH2) found in human signaling and regulatory proteins. Several motifs overlap in the tail sequences, suggesting that they may act as molecular switches, such as in response to tyrosine phosphorylation status. Candidate LC3-interacting region (LIR) motifs are present in the tails of integrin β
MeSH term(s)	Amino Acid Sequence ; Angiotensin-Converting Enzyme 2/chemistry ; Angiotensin-Converting Enzyme 2/genetics ; Angiotensin-Converting Enzyme 2/physiology ; Animals ; COVID-19/therapy ; COVID-19/virology ; Conserved Sequence ; Host Microbial Interactions/genetics ; Host Microbial Interactions/physiology ; Humans ; Integrins/chemistry ; Integrins/genetics ; Integrins/physiology ; Intrinsically Disordered Proteins/chemistry ; Intrinsically Disordered Proteins/genetics ; Intrinsically Disordered Proteins/physiology ; Models, Biological ; Models, Molecular ; Oligopeptides/chemistry ; Oligopeptides/genetics ; Oligopeptides/physiology ; Protein Interaction Domains and Motifs/genetics ; Protein Interaction Domains and Motifs/physiology ; Protein Sorting Signals/genetics ; Protein Sorting Signals/physiology ; Receptors, Virus/chemistry ; Receptors, Virus/genetics ; Receptors, Virus/physiology ; SARS-CoV-2/genetics ; SARS-CoV-2/pathogenicity ; SARS-CoV-2/physiology ; Spike Glycoprotein, Coronavirus/chemistry ; Spike Glycoprotein, Coronavirus/genetics ; Spike Glycoprotein, Coronavirus/physiology ; Virus Internalization
Chemical Substances	Integrins ; Intrinsically Disordered Proteins ; Oligopeptides ; Protein Sorting Signals ; Receptors, Virus ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 ; arginyl-glycyl-aspartic acid (78VO7F77PN) ; ACE2 protein, human (EC 3.4.17.23) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23)
Language	English
Publishing date	2021-01-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2417226-1
ISSN	1937-9145 ; 1945-0877
ISSN (online)	1937-9145
ISSN	1945-0877
DOI	10.1126/scisignal.abd0334
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Article ; Online: PDZ Domains as Drug Targets.

Christensen, Nikolaj R / Čalyševa, Jelena / Fernandes, Eduardo F A / Lüchow, Susanne / Clemmensen, Louise S / Haugaard-Kedström, Linda M / Strømgaard, Kristian

Advanced therapeutics

2019 Volume 2, Issue 7, Page(s) 1800143

Abstract: Protein-protein interactions within protein networks shape the human interactome, which often is promoted by specialized protein interaction modules, such as the postsynaptic density-95 (PSD-95), discs-large, zona occludens 1 (ZO-1) (PDZ) domains. PDZ ... ...

Abstract	Protein-protein interactions within protein networks shape the human interactome, which often is promoted by specialized protein interaction modules, such as the postsynaptic density-95 (PSD-95), discs-large, zona occludens 1 (ZO-1) (PDZ) domains. PDZ domains play a role in several cellular functions, from cell-cell communication and polarization, to regulation of protein transport and protein metabolism. PDZ domain proteins are also crucial in the formation and stability of protein complexes, establishing an important bridge between extracellular stimuli detected by transmembrane receptors and intracellular responses. PDZ domains have been suggested as promising drug targets in several diseases, ranging from neurological and oncological disorders to viral infections. In this review, the authors describe structural and genetic aspects of PDZ-containing proteins and discuss the current status of the development of small-molecule and peptide modulators of PDZ domains. An overview of potential new therapeutic interventions in PDZ-mediated protein networks is also provided.
Keywords	covid19
Language	English
Publishing date	2019-04-24
Publishing country	Germany
Document type	Journal Article ; Review
ISSN	2366-3987
ISSN (online)	2366-3987
DOI	10.1002/adtp.201800143
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: How to Annotate and Submit a Short Linear Motif to the Eukaryotic Linear Motif Resource.

Gouw, Marc / Alvarado-Valverde, Jesús / Čalyševa, Jelena / Diella, Francesca / Kumar, Manjeet / Michael, Sushama / Van Roey, Kim / Dinkel, Holger / Gibson, Toby J

Methods in molecular biology (Clifton, N.J.)

2020 Volume 2141, Page(s) 73–102

Abstract: Over the past few years, it has become apparent that approximately 35% of the human proteome consists of intrinsically disordered regions. Many of these disordered regions are rich in short linear motifs (SLiMs) which mediate protein-protein interactions. ...

Abstract	Over the past few years, it has become apparent that approximately 35% of the human proteome consists of intrinsically disordered regions. Many of these disordered regions are rich in short linear motifs (SLiMs) which mediate protein-protein interactions. Although these motifs are short and often partially conserved, they are involved in many important aspects of protein function, including cleavage, targeting, degradation, docking, phosphorylation, and other posttranslational modifications. The Eukaryotic Linear Motif resource (ELM) was established over 15 years ago as a repository to store and catalogue the scientific discoveries of motifs. Each motif in the database is annotated and curated manually, based on the experimental evidence gathered from publications. The entries themselves are submitted to ELM by filling in two annotation templates designed for motif class and motif instance annotation. In this protocol, we describe the steps involved in annotating new motifs and how to submit them to ELM.
MeSH term(s)	Amino Acid Motifs ; Eukaryota/metabolism ; Molecular Sequence Annotation/methods ; Proteins/chemistry ; Software
Chemical Substances	Proteins
Language	English
Publishing date	2020-07-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-0524-0_4
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: UbaLAI is a monomeric Type IIE restriction enzyme.

Sasnauskas, Giedrius / Tamulaitiene, Giedre / Tamulaitis, Gintautas / Calyševa, Jelena / Laime, Migle / Rimšeliene, Renata / Lubys, Arvydas / Siksnys, Virginijus

Nucleic acids research

2017 Volume 45, Issue 16, Page(s) 9583–9594

Abstract: Type II restriction endonucleases (REases) form a large and highly diverse group of enzymes. Even REases specific for a common recognition site often vary in their oligomeric structure, domain organization and DNA cleavage mechanisms. Here we report ... ...

Abstract	Type II restriction endonucleases (REases) form a large and highly diverse group of enzymes. Even REases specific for a common recognition site often vary in their oligomeric structure, domain organization and DNA cleavage mechanisms. Here we report biochemical and structural characterization of the monomeric restriction endonuclease UbaLAI, specific for the pseudosymmetric DNA sequence 5'-CC/WGG-3' (where W = A/T, and '/' marks the cleavage position). We present a 1.6 Å co-crystal structure of UbaLAI N-terminal domain (UbaLAI-N) and show that it resembles the B3-family domain of EcoRII specific for the 5'-CCWGG-3' sequence. We also find that UbaLAI C-terminal domain (UbaLAI-C) is closely related to the monomeric REase MvaI, another enzyme specific for the 5'-CCWGG-3' sequence. Kinetic studies of UbaLAI revealed that it requires two recognition sites for optimal activity, and, like other type IIE enzymes, uses one copy of a recognition site to stimulate cleavage of a second copy. We propose that during the reaction UbaLAI-N acts as a handle that tethers the monomeric UbaLAI-C domain to the DNA, thereby helping UbaLAI-C to perform two sequential DNA nicking reactions on the second recognition site during a single DNA-binding event. A similar reaction mechanism may be characteristic to other monomeric two-domain REases.
MeSH term(s)	Crystallography, X-Ray ; DNA/chemistry ; DNA/metabolism ; DNA Cleavage ; Deoxyribonucleases, Type II Site-Specific/chemistry ; Deoxyribonucleases, Type II Site-Specific/genetics ; Deoxyribonucleases, Type II Site-Specific/metabolism ; Models, Molecular ; Protein Domains ; Substrate Specificity
Chemical Substances	DNA (9007-49-2) ; Deoxyribonucleases, Type II Site-Specific (EC 3.1.21.4)
Language	English
Publishing date	2017-09-07
Publishing country	England
Document type	Journal Article
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkx634
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Zs.A 1067: Show issues

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Article ; Online: ELM-the eukaryotic linear motif resource in 2020.

Kumar, Manjeet / Gouw, Marc / Michael, Sushama / Sámano-Sánchez, Hugo / Pancsa, Rita / Glavina, Juliana / Diakogianni, Athina / Valverde, Jesús Alvarado / Bukirova, Dayana / Čalyševa, Jelena / Palopoli, Nicolas / Davey, Norman E / Chemes, Lucía B / Gibson, Toby J

Nucleic acids research

2019 Volume 48, Issue D1, Page(s) D296–D306

Abstract: The eukaryotic linear motif (ELM) resource is a repository of manually curated experimentally validated short linear motifs (SLiMs). Since the initial release almost 20 years ago, ELM has become an indispensable resource for the molecular biology ... ...

Abstract	The eukaryotic linear motif (ELM) resource is a repository of manually curated experimentally validated short linear motifs (SLiMs). Since the initial release almost 20 years ago, ELM has become an indispensable resource for the molecular biology community for investigating functional regions in many proteins. In this update, we have added 21 novel motif classes, made major revisions to 12 motif classes and added >400 new instances mostly focused on DNA damage, the cytoskeleton, SH2-binding phosphotyrosine motifs and motif mimicry by pathogenic bacterial effector proteins. The current release of the ELM database contains 289 motif classes and 3523 individual protein motif instances manually curated from 3467 scientific publications. ELM is available at: http://elm.eu.org.
MeSH term(s)	Amino Acid Motifs ; Apicoplasts/metabolism ; Cytoskeleton ; DNA Damage ; Databases, Protein ; Eukaryota ; Phosphotyrosine ; src Homology Domains
Chemical Substances	Phosphotyrosine (21820-51-9)
Language	English
Publishing date	2019-11-04
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkz1030
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Book ; Online: Short linear motif candidates in the cell entry system used by SARS-CoV-2 and their potential therapeutic implications

Mészáros, Bálint / Sámano-Sánchez, Hugo / Alvarado-Valverde, Jesús / Čalyševa, Jelena / Martínez-Pérez, Elizabeth / Alves, Renato / Kumar, Manjeet / Rippmann, Friedrich / Chemes, Lucía B. / Gibson, Toby J. / .

2020

Abstract: The primary cell surface receptor for SARS-CoV-2 is the angiotensin-converting enzyme 2 (ACE2). Recently it has been noticed that the viral Spike protein has an RGD motif, suggesting that cell surface integrins may be co-receptors. We examined the ... ...

Abstract	The primary cell surface receptor for SARS-CoV-2 is the angiotensin-converting enzyme 2 (ACE2). Recently it has been noticed that the viral Spike protein has an RGD motif, suggesting that cell surface integrins may be co-receptors. We examined the sequences of ACE2 and integrins with the Eukaryotic Linear Motif resource, ELM, and were presented with candidate short linear motifs (SLiMs) in their short, unstructured, cytosolic tails with potential roles in endocytosis, membrane dynamics, autophagy, cytoskeleton and cell signalling. These SLiM candidates are highly conserved in vertebrates. They suggest potential interactions with the AP2 mu2 subunit as well as I-BAR, LC3, PDZ, PTB and SH2 domains found in signalling and regulatory proteins present in epithelial lung cells. Several motifs overlap in the tail sequences, suggesting that they may act as molecular switches, often involving tyrosine phosphorylation status. Candidate LIR motifs are present in the tails of ACE2 and integrin beta3, suggesting that these proteins can directly recruit autophagy components. We also noticed that the extracellular part of ACE2 has a conserved MIDAS structural motif, which are commonly used by beta integrins for ligand binding, potentially supporting the proposal that integrins and ACE2 share common ligands. The findings presented here identify several molecular links and testable hypotheses that might help uncover the mechanisms of SARS-CoV-2 attachment, entry and replication, and strengthen the possibility that it might be possible to develop host-directed therapies to dampen the efficiency of viral entry and hamper disease progression. The strong sequence conservation means that these putative SLiMs are good candidates: Nevertheless, SLiMs must always be validated by experimentation before they can be stated to be functional. Comment: 38 pages, 7 figures, 2 tables. Corresponding authors are Luc\'ia B. Chemes, Toby J. Gibson
Keywords	Quantitative Biology - Biomolecules
Subject code	570
Publishing date	2020-04-21
Publishing country	us
Document type	Book ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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