Pfam: The protein families database in 2021

Mistry, Jaina; Chuguransky, Sara; Williams, Lowri; Qureshi, Matloob; Salazar, Gustavo; Sonnhammer, Erik L. L.; Tosatto, Silvio C. E.; Paladin, Lisanna; Raj, Shriya; Richardson, Lorna; Finn, Robert D.

doi:10.1093/nar/gkaa913

Cited by 4,289 publications

(3,396 citation statements)

References 27 publications

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“…Domain annotations for one representative bacterial CSP and human CSD-containing proteins according to SMART [ 27 ]. For CSDE1, Pfam [ 31 ] agrees with the domain annotation shown here. Uniprot [ 22 ] annotates two additional CSDs in CSDE1, one between CSD3 and CSD4 and one between CSD4 and CSD5, as well as two additional truncated CSDs, one between CSD1 and CSD2 and one between CSD2 and CSD3.…”

Section: Figuresupporting

confidence: 70%

Cold-Shock Domains—Abundance, Structure, Properties, and Nucleic-Acid Binding

Heinemann

Roske

2021

Cancers

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The cold-shock domain has a deceptively simple architecture but supports a complex biology. It is conserved from bacteria to man and has representatives in all kingdoms of life. Bacterial cold-shock proteins consist of a single cold-shock domain and some, but not all are induced by cold shock. Cold-shock domains in human proteins are often associated with natively unfolded protein segments and more rarely with other folded domains. Cold-shock proteins and domains share a five-stranded all-antiparallel β-barrel structure and a conserved surface that binds single-stranded nucleic acids, predominantly by stacking interactions between nucleobases and aromatic protein sidechains. This conserved binding mode explains the cold-shock domains’ ability to associate with both DNA and RNA strands and their limited sequence selectivity. The promiscuous DNA and RNA binding provides a rationale for the ability of cold-shock domain-containing proteins to function in transcription regulation and DNA-damage repair as well as in regulating splicing, translation, mRNA stability and RNA sequestration.

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Section: Figuresupporting

confidence: 70%

Cold-Shock Domains—Abundance, Structure, Properties, and Nucleic-Acid Binding

Heinemann

Roske

2021

Cancers

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“…Domains were predicted using the same Hmmsearch procedure against the Pfam database (version 33.0) 49 . SIGNALP (version 5.0) was run to predict the putative cellular localization of the proteins using the parameters -org arch in archaeal genomes and -org gram+ in bacterial genomes 50 .…”

Section: Functional Annotationmentioning

confidence: 99%

Post-translational flavinylation is associated with diverse extracytosolic redox functionalities throughout bacterial life

Méheust

Huang

Rivera‐Lugo

et al. 2021

Preprint

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Disparate redox biochemistries that take place beyond the bounds of the prokaryotic cell cytosol must connect to membrane or cytosolic electron pools. Proteins post-translationally flavinylated by the enzyme ApbE mediate electron transfer in several characterized extracytosolic redox biochemistries but the breadth of functions of this modification remains unknown. Here we present a comprehensive bioinformatic analysis of 31,910 prokaryotic genomes that provides evidence of extracytosolic ApbEs within ~50% of bacteria and the involvement of flavinylation in numerous uncharacterized biochemistries. By mining flavinylation-associated gene clusters, we identify five protein classes responsible for transmembrane electron transfer and two domains of unknown function (DUF2271 and DUF3570) that are flavinylated by ApbE. We observe flavinylation/iron transporter gene colocalization patterns that suggest functions in iron reduction and assimilation. We find associations with characterized and uncharacterized respiratory oxidoreductases that highlight roles of flavinylation in respiratory electron transport chains. Finally, we identify interspecies gene cluster variability consistent with flavinylation/cytochrome functional redundancies and discover a class of “multi-flavinylated proteins” that may resemble multiheme cytochromes in facilitating longer distance electron transfer. These findings provide mechanistic insight into an important facet of bacterial physiology and establish flavinylation as a functionally diverse mediator of extracytosolic electron transfer.

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“…66,67 We employed Kullback-Leibler (KL) sequence conservation score KLConsScore using MSA profiles generated by hidden Markov models in Pfam database for the SARS-CoV S glycoproteins. 68,69 Three Pfam domains were utilized corresponding to S1, the NTD (bCoV_S1_N, Betacoronavirus-like spike glycoprotein S1, Nterminal, Pfam:PF16451, Uniprot SPIKE_CVHSA, pdb id 6CS0, residues 33-324), the RBD The KL conservation is calculated according to the following formula:…”

Section: Sequence Conservation and Coevolutionary Analysesmentioning

confidence: 99%

Coevolutionary Analysis and Perturbation-Based Network Modeling of the SARS-CoV-2 Spike Protein Complexes with Antibodies: Binding-Induced Control of Dynamics, Allosteric Interactions and Signaling

Verkhivker

Paola

2021

Preprint

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The structural and biochemical studies of the SARS-CoV-2 spike glycoproteins and complexes with highly potent antibodies have revealed multiple conformation-dependent epitopes highlighting the link between conformational plasticity of spike proteins and capacity for eliciting specific binding and broad neutralization responses. In this study, we used coevolutionary analysis, molecular simulations, and perturbation-based hierarchical network modeling of the SARS-CoV-2 S complexes with H014, S309, S2M11 and S2E12 antibodies targeting distinct epitopes to explore molecular mechanisms underlying binding-induced modulation of dynamics, stability and allosteric signaling in the spike protein trimers. The results of this study revealed key regulatory centers that can govern allosteric interactions and communications in the SARS-CoV-2 spike proteins. Through coevolutionary analysis of the SARS-CoV-2 spike proteins, we identified highly coevolving hotspots and functional clusters forming coevolutionary networks. The results revealed significant coevolutionary couplings between functional regions separated by the medium-range distances which may help to facilitate a functional cross-talk between distant allosteric regions in the SARS-CoV-2 spike complexes with antibodies. We also discovered a potential mechanism by which antibody-specific targeting of coevolutionary centers can allow for efficient modulation of allosteric interactions and signal propagation between remote functional regions. Using a hierarchical network modeling and perturbation-response scanning analysis, we demonstrated that binding of antibodies could leverage direct contacts with coevolutionary hotspots to allosterically restore and enhance couplings between spatially separated functional regions, thereby protecting the spike apparatus from membrane fusion. The results of this study also suggested that antibody binding can induce a switch from a moderately cooperative population-shift mechanism, governing structural changes of the ligand-free SARS-CoV-2 spike protein, to antibody-induced highly cooperative mechanism that can better withstand mutations in the functional regions without significant deleterious consequences for protein function. This study provides a novel insight into allosteric regulatory mechanisms of SARS-CoV-2 S proteins, showing that antibodies can modulate allosteric interactions and signaling of spike proteins, providing a plausible strategy for therapeutic intervention by targeting specific hotspots of allosteric interactions in the SARS-CoV-2 proteins.

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Pfam: The protein families database in 2021

Cited by 4,289 publications

References 27 publications

Cold-Shock Domains—Abundance, Structure, Properties, and Nucleic-Acid Binding

Cold-Shock Domains—Abundance, Structure, Properties, and Nucleic-Acid Binding

Post-translational flavinylation is associated with diverse extracytosolic redox functionalities throughout bacterial life

Coevolutionary Analysis and Perturbation-Based Network Modeling of the SARS-CoV-2 Spike Protein Complexes with Antibodies: Binding-Induced Control of Dynamics, Allosteric Interactions and Signaling

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