Affinage

Showing SH2D3C — NSP3 is a alias.

SH2D3C

SH2 domain-containing protein 3C · UniProt Q8N5H7

Length
860 aa
Mass
94.4 kDa
Annotated
2026-06-10
100 papers in source corpus 1 papers cited in narrative 1 extracted findings
Cross-family judge vs UniProt: UniProt preferred faithfulness: 1/1 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Mechanistic understanding of human SH2D3C (NSP3) rests on a single computational study, which used molecular docking and molecular dynamics simulation to predict that NSP3 interacts with p130Cas to form a multi-domain signaling platform, and that the substitutions L469R, L623E, and R627E would reduce p130Cas binding affinity, with L469R causing the largest structural deviation and increased conformational flexibility (PMID:23494262). Beyond this in silico prediction, no wet-lab biochemical, cellular, or structural characterization of SH2D3C has been established in the available corpus.

Mechanistic history

Synthesis pass · year-by-year structured walk · 1 step
  1. 2013 Low

    To address whether NSP3 could physically engage p130Cas in a signaling complex, an in silico study modeled the interaction and the effect of point mutations, establishing a candidate binding interface and residues predicted to be critical for affinity.

    Evidence Computational molecular docking and molecular dynamics simulation, no wet-lab validation

    PMID:23494262

    Open questions at the time
    • Purely computational; the predicted NSP3-p130Cas interaction has not been confirmed by any biochemical or cellular assay
    • No experimental validation of the L469R, L623E, or R627E mutational effects on binding
    • No determination of the cellular context, localization, or downstream signaling role of the predicted complex

Open questions

Synthesis pass · forward-looking unresolved questions
  • Whether SH2D3C physically binds p130Cas in cells and what signaling or cellular function this complex serves remains entirely uncharacterized experimentally.
  • No reconstitution or co-immunoprecipitation confirming the interaction
  • No defined molecular activity, localization, or pathway assignment
  • No loss-of-function phenotype reported

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
No controlled-vocabulary terms were assigned to this entry.

Evidence

Reading pass · 1 per-paper finding extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 Computational modeling predicted that human SH2D3C (NSP3) interacts with p130Cas to form a multi-domain signaling platform; mutations NSP3(L469R), NSP3(L623E), and NSP3(R627E) were predicted to reduce binding affinity to p130Cas, with NSP3(L469R) showing the most significant structural deviation and increased conformational flexibility by molecular dynamics simulation. Computational molecular docking and molecular dynamics simulation (in silico only; no wet-lab validation reported) Cell biochemistry and biophysics Low 23494262

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 Nsp3 of coronaviruses: Structures and functions of a large multi-domain protein. Antiviral research 484 29128390
1998 Rotavirus RNA-binding protein NSP3 interacts with eIF4GI and evicts the poly(A) binding protein from eIF4F. The EMBO journal 283 9755181
2020 COVID-2019: The role of the nsp2 and nsp3 in its pathogenesis. Journal of medical virology 213 32083328
2017 Expression and Cleavage of Middle East Respiratory Syndrome Coronavirus nsp3-4 Polyprotein Induce the Formation of Double-Membrane Vesicles That Mimic Those Associated with Coronaviral RNA Replication. mBio 206 29162711
2009 The crystal structures of Chikungunya and Venezuelan equine encephalitis virus nsP3 macro domains define a conserved adenosine binding pocket. Journal of virology 194 19386706
2021 Fragment binding to the Nsp3 macrodomain of SARS-CoV-2 identified through crystallographic screening and computational docking. Science advances 166 33853786
2005 Structural basis of severe acute respiratory syndrome coronavirus ADP-ribose-1''-phosphate dephosphorylation by a conserved domain of nsP3. Structure (London, England : 1993) 163 16271890
2012 Chikungunya virus nsP3 blocks stress granule assembly by recruitment of G3BP into cytoplasmic foci. Journal of virology 156 22837213
2000 Efficient translation of rotavirus mRNA requires simultaneous interaction of NSP3 with the eukaryotic translation initiation factor eIF4G and the mRNA 3' end. Journal of virology 146 10888646
2014 The nsp3 macrodomain promotes virulence in mice with coronavirus-induced encephalitis. Journal of virology 143 25428866
2008 Phylogenetic analyses and molecular epidemiology of European salmonid alphaviruses (SAV) based on partial E2 and nsP3 gene nucleotide sequences. Journal of fish diseases 124 18681902
2008 Different types of nsP3-containing protein complexes in Sindbis virus-infected cells. Journal of virology 123 18684830
2018 ADP-ribosyl-binding and hydrolase activities of the alphavirus nsP3 macrodomain are critical for initiation of virus replication. Proceedings of the National Academy of Sciences of the United States of America 122 30322911
2006 Formation of nsP3-specific protein complexes during Sindbis virus replication. Journal of virology 122 16571828
2008 The SARS-Coronavirus PLnc domain of nsp3 as a replication/transcription scaffolding protein. Virus research 110 18255185
2011 SH3 domain-mediated recruitment of host cell amphiphysins by alphavirus nsP3 promotes viral RNA replication. PLoS pathogens 109 22114558
2002 Recognition of eIF4G by rotavirus NSP3 reveals a basis for mRNA circularization. Molecular cell 108 12086624
2018 The Enigmatic Alphavirus Non-Structural Protein 3 (nsP3) Revealing Its Secrets at Last. Viruses 105 29495654
2014 Catalytic function and substrate specificity of the papain-like protease domain of nsp3 from the Middle East respiratory syndrome coronavirus. Journal of virology 104 25142582
1994 Genetic analysis of the nsP3 region of Sindbis virus: evidence for roles in minus-strand and subgenomic RNA synthesis. Journal of virology 99 8057460
1994 Alphavirus nsP3 functions to form replication complexes transcribing negative-strand RNA. Journal of virology 97 8083984
2023 Iterative computational design and crystallographic screening identifies potent inhibitors targeting the Nsp3 macrodomain of SARS-CoV-2. Proceedings of the National Academy of Sciences of the United States of America 96 36598939
2021 The SARS-CoV-2 Nsp3 macrodomain reverses PARP9/DTX3L-dependent ADP-ribosylation induced by interferon signaling. The Journal of biological chemistry 95 34358560
2020 Molecular Basis for ADP-Ribose Binding to the Mac1 Domain of SARS-CoV-2 nsp3. Biochemistry 95 32578982
2015 Differential Phosphatidylinositol-3-Kinase-Akt-mTOR Activation by Semliki Forest and Chikungunya Viruses Is Dependent on nsP3 and Connected to Replication Complex Internalization. Journal of virology 89 26339054
2013 Chikungunya virus nsP3 & nsP4 interacts with HSP-90 to promote virus replication: HSP-90 inhibitors reduce CHIKV infection and inflammation in vivo. Antiviral research 88 24388965
2009 The nsP3 macro domain is important for Sindbis virus replication in neurons and neurovirulence in mice. Virology 88 19395054
2002 Recognition of the rotavirus mRNA 3' consensus by an asymmetric NSP3 homodimer. Cell 85 11792322
1988 Semliki Forest virus-specific non-structural protein nsP3 is a phosphoprotein. The Journal of general virology 85 2970523
1990 Phosphorylation of Sindbis virus nsP3 in vivo and in vitro. Virology 84 2145690
2014 The C-terminal repeat domains of nsP3 from the Old World alphaviruses bind directly to G3BP. Journal of virology 83 24623412
1994 Products of the porcine group C rotavirus NSP3 gene bind specifically to double-stranded RNA and inhibit activation of the interferon-induced protein kinase PKR. Journal of virology 82 7514679
1993 Rotavirus protein NSP3 (NS34) is bound to the 3' end consensus sequence of viral mRNAs in infected cells. Journal of virology 80 8388495
2008 Nuclear localization of cytoplasmic poly(A)-binding protein upon rotavirus infection involves the interaction of NSP3 with eIF4G and RoXaN. Journal of virology 78 18799579
2023 SARS-CoV-2 nsp3 and nsp4 are minimal constituents of a pore spanning replication organelle. Nature communications 77 38036567
1999 Identification of the RNA-binding, dimerization, and eIF4GI-binding domains of rotavirus nonstructural protein NSP3. Journal of virology 77 10364288
1988 Nonstructural proteins nsP3 and nsP4 of Ross River and O'Nyong-nyong viruses: sequence and comparison with those of other alphaviruses. Virology 71 2834873
1994 Deletion and duplication mutations in the C-terminal nonconserved region of Sindbis virus nsP3: effects on phosphorylation and on virus replication in vertebrate and invertebrate cells. Virology 68 7912020
2019 Multiple roles of the non-structural protein 3 (nsP3) alphavirus unique domain (AUD) during Chikungunya virus genome replication and transcription. PLoS pathogens 66 30668592
2012 Hypervariable domains of nsP3 proteins of New World and Old World alphaviruses mediate formation of distinct, virus-specific protein complexes. Journal of virology 66 23221551
1994 Four nucleotides are the minimal requirement for RNA recognition by rotavirus non-structural protein NSP3. The EMBO journal 65 8076612
2021 Biochemical characterization of protease activity of Nsp3 from SARS-CoV-2 and its inhibition by nanobodies. PloS one 64 34270554
2000 Elimination of phosphorylation sites of Semliki Forest virus replicase protein nsP3. The Journal of biological chemistry 64 11104756
2016 Combined structural, biochemical and cellular evidence demonstrates that both FGDF motifs in alphavirus nsP3 are required for efficient replication. Open biology 63 27383630
2006 Rotavirus Nonstructural Protein NSP3 is not required for viral protein synthesis. Journal of virology 63 16940515
2018 Multiple Host Factors Interact with the Hypervariable Domain of Chikungunya Virus nsP3 and Determine Viral Replication in Cell-Specific Mode. Journal of virology 62 29899097
2021 SARS-CoV-2 Nsp3 unique domain SUD interacts with guanine quadruplexes and G4-ligands inhibit this interaction. Nucleic acids research 57 34232992
2020 Both ADP-Ribosyl-Binding and Hydrolase Activities of the Alphavirus nsP3 Macrodomain Affect Neurovirulence in Mice. mBio 56 32047134
2003 Functional analysis of nsP3 phosphoprotein mutants of Sindbis virus. Journal of virology 56 14645567
2021 Targeting SARS-CoV-2 Nsp3 macrodomain structure with insights from human poly(ADP-ribose) glycohydrolase (PARG) structures with inhibitors. Progress in biophysics and molecular biology 53 33636189
2011 Rotavirus infection induces the unfolded protein response of the cell and controls it through the nonstructural protein NSP3. Journal of virology 53 21937647
2019 Generation of Recombinant Rotavirus Expressing NSP3-UnaG Fusion Protein by a Simplified Reverse Genetics System. Journal of virology 52 31597761
2017 Hypervariable Domain of Eastern Equine Encephalitis Virus nsP3 Redundantly Utilizes Multiple Cellular Proteins for Replication Complex Assembly. Journal of virology 52 28468889
2003 Amino acid mutations in the replicase protein nsP3 of Semliki Forest virus cumulatively affect neurovirulence. The Journal of general virology 51 12771422
2010 Molecular insight into the specific binding of ADP-ribose to the nsP3 macro domains of chikungunya and Venezuelan equine encephalitis viruses: molecular dynamics simulations and free energy calculations. Journal of molecular graphics & modelling 48 21036084
2021 Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of Nsp3 papain-like protease. The Biochemical journal 45 34198325
2022 The mechanisms of catalysis and ligand binding for the SARS-CoV-2 NSP3 macrodomain from neutron and x-ray diffraction at room temperature. Science advances 44 35622909
2015 Mosquito Rasputin interacts with chikungunya virus nsP3 and determines the infection rate in Aedes albopictus. Parasites & vectors 42 26384002
2020 Discovery of Drug-Like Ligands for the Mac1 Domain of SARS-CoV-2 Nsp3. SLAS discovery : advancing life sciences R & D 41 32981460
2013 Hypervariable domain of nonstructural protein nsP3 of Venezuelan equine encephalitis virus determines cell-specific mode of virus replication. Journal of virology 41 23637407
2020 A Putative Role of de-Mono-ADP-Ribosylation of STAT1 by the SARS-CoV-2 Nsp3 Protein in the Cytokine Storm Syndrome of COVID-19. Viruses 40 32549200
2018 Sindbis Virus Infection Causes Cell Death by nsP2-Induced Transcriptional Shutoff or by nsP3-Dependent Translational Shutoff. Journal of virology 40 30232189
2020 SARS-CoV-2 nucleocapsid and Nsp3 binding: an in silico study. Archives of microbiology 39 32749662
2018 Mutation of CD2AP and SH3KBP1 Binding Motif in Alphavirus nsP3 Hypervariable Domain Results in Attenuated Virus. Viruses 38 29702546
2001 A human rotavirus with rearranged genes 7 and 11 encodes a modified NSP3 protein and suggests an additional mechanism for gene rearrangement. Journal of virology 37 11462002
2009 Novel functions of the alphavirus nonstructural protein nsP3 C-terminal region. Journal of virology 36 20015978
1996 Complete sequence of Venezuelan equine encephalitis virus subtype IE reveals conserved and hypervariable domains within the C terminus of nsP3. Virology 36 8623548
2016 Analysis of chikungunya virus proteins reveals that non-structural proteins nsP2 and nsP3 exhibit RNA interference (RNAi) suppressor activity. Scientific reports 35 27901124
2015 Rotavirus NSP3 Is a Translational Surrogate of the Poly(A) Binding Protein-Poly(A) Complex. Journal of virology 35 26063427
2000 Rearrangement generated in double genes, NSP1 and NSP3, of viable progenies from a human rotavirus strain. Virus research 35 10867195
1995 Comparative nucleotide and amino acid sequence analysis of the sequence-specific RNA-binding rotavirus nonstructural protein NSP3. Virology 35 7871749
2002 Rotavirus protein NSP3 shuts off host cell protein synthesis. Virology 34 12093167
2016 Structural Basis of the High Affinity Interaction between the Alphavirus Nonstructural Protein-3 (nsP3) and the SH3 Domain of Amphiphysin-2. The Journal of biological chemistry 33 27268056
2004 RoXaN, a novel cellular protein containing TPR, LD, and zinc finger motifs, forms a ternary complex with eukaryotic initiation factor 4G and rotavirus NSP3. Journal of virology 33 15047801
2016 Venezuelan equine encephalitis virus non-structural protein 3 (nsP3) interacts with RNA helicases DDX1 and DDX3 in infected cells. Antiviral research 32 27105836
2006 Deletions in the hypervariable domain of the nsP3 gene attenuate Semliki Forest virus virulence. The Journal of general virology 31 16528043
2018 Interactions of Alphavirus nsP3 Protein with Host Proteins. Frontiers in microbiology 30 29375517
2014 Discovery of in silico hits targeting the nsP3 macro domain of chikungunya virus. Journal of molecular modeling 30 24756552
2023 A single inactivating amino acid change in the SARS-CoV-2 NSP3 Mac1 domain attenuates viral replication in vivo. PLoS pathogens 29 37651466
2019 Evaluation of the Antiviral Potential of Halogenated Dihydrorugosaflavonoids and Molecular Modeling with nsP3 Protein of Chikungunya Virus (CHIKV). ACS omega 28 31815237
2022 Design, synthesis and evaluation of inhibitors of the SARS-CoV-2 nsp3 macrodomain. Bioorganic & medicinal chemistry 27 35597097
2019 Involvement of PRRSV NSP3 and NSP5 in the autophagy process. Virology journal 27 30691473
2023 Nsp3-N interactions are critical for SARS-CoV-2 fitness and virulence. Proceedings of the National Academy of Sciences of the United States of America 26 37487098
2020 Expression of Separate Heterologous Proteins from the Rotavirus NSP3 Genome Segment Using a Translational 2A Stop-Restart Element. Journal of virology 26 32611753
2015 X-ray Structural and Functional Studies of the Three Tandemly Linked Domains of Non-structural Protein 3 (nsp3) from Murine Hepatitis Virus Reveal Conserved Functions. The Journal of biological chemistry 26 26296883
2024 Alphavirus nsP3 organizes into tubular scaffolds essential for infection and the cytoplasmic granule architecture. Nature communications 25 39285216
2012 Rotavirus variant replicates efficiently although encoding an aberrant NSP3 that fails to induce nuclear localization of poly(A)-binding protein. The Journal of general virology 24 22442114
2011 Active participation of cellular chaperone Hsp90 in regulating the function of rotavirus nonstructural protein 3 (NSP3). The Journal of biological chemistry 24 21489987
2021 Phosphorylation Sites in the Hypervariable Domain in Chikungunya Virus nsP3 Are Crucial for Viral Replication. Journal of virology 23 33568506
2013 Investigation of binding phenomenon of NSP3 and p130Cas mutants and their effect on cell signalling. Cell biochemistry and biophysics 23 23494262
2020 Is the ADP ribose site of the Chikungunya virus NSP3 Macro domain a target for antiviral approaches? Acta tropica 21 32333884
2019 A model to study the inhibition of nsP2B-nsP3 protease of dengue virus with imidazole, oxazole, triazole thiadiazole, and thiazolidine based scaffolds. Heliyon 21 31406937
2015 Development of novel antibodies against non-structural proteins nsP1, nsP3 and nsP4 of chikungunya virus: potential use in basic research. Archives of virology 21 26280524
2023 Discovery and Development Strategies for SARS-CoV-2 NSP3 Macrodomain Inhibitors. Pathogens (Basel, Switzerland) 20 36839595
2022 Molecular modelling and structure-activity relationship of a natural derivative of o-hydroxybenzoate as a potent inhibitor of dual NSP3 and NSP12 of SARS-CoV-2: in silico study. Journal of biomolecular structure & dynamics 20 35037841
2021 NAP1L1 and NAP1L4 Binding to Hypervariable Domain of Chikungunya Virus nsP3 Protein Is Bivalent and Requires Phosphorylation. Journal of virology 19 34076483
2020 Hypervariable Domain of nsP3 of Eastern Equine Encephalitis Virus Is a Critical Determinant of Viral Virulence. Journal of virology 19 32581106
2020 Venezuelan Equine Encephalitis Virus nsP3 Phosphorylation Can Be Mediated by IKKβ Kinase Activity and Abrogation of Phosphorylation Inhibits Negative-Strand Synthesis. Viruses 19 32933112
2019 Structural characterization and biological function of bivalent binding of CD2AP to intrinsically disordered domain of chikungunya virus nsP3 protein. Virology 19 31493651
2010 Lineage replacement accompanying duplication and rapid fixation of an RNA element in the nsP3 gene in a species of alphavirus. Virology 19 21185049

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