ELM--the database of eukaryotic linear motifs

Dinkel, Holger; Michael, Sushama; Weatheritt, Robert J.; Davey, Norman E.; Roey, Kim Van; Altenberg, Brigitte; Toedt, Grischa; Uyar, Bora; Seiler, Markus; Budd, Aidan; Jödicke, Lisa; Dammert, Marcel A.; Schroeter, Christian; Hammer, Maria; Schmidt, Tuany Rafaeli; Jehl, Peter; McGuigan, Caroline; Dymecka, Magdalena; Chica, Claudia; Luck, Katja; Via, Allegra; Chatr‐aryamontri, Andrew; Haslam, Niall; Grebnev, Gleb; Edwards, Richard J.; Steinmetz, Michel O.; Meiselbach, Heike; Diella, Francesca; Gibson, Toby J.

doi:10.1093/nar/gkr1064

Cited by 308 publications

(329 citation statements)

References 42 publications

(48 reference statements)

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“…3A to F, 4B, and 6C to F). The results suggest that (10,8,18,21,25,11,18, and 26 cells for the columns going from left to right, respectively), and the ratio of the MFI in the nucleus to the MFI in the total cell was determined and expressed as a percentage (mean Ϯ standard deviation). (K to Q) Subcellular localization of FIV MA-CFP, CA-CFP, and NCp2-CFP.…”

Section: Discussionmentioning

confidence: 96%

Feline Immunodeficiency Virus Gag Is a Nuclear Shuttling Protein

Kemler

Saenz

Poeschla

2012

J Virol

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Lentiviral genomic RNAs are encapsidated by the viral Gag protein during virion assembly. The intracellular location of the initial Gag-RNA interaction is unknown. We previously observed feline immunodeficiency virus (FIV) Gag accumulating at the nuclear envelope during live-cell imaging, which suggested that trafficking of human immunodeficiency virus type 1 (HIV-1) and FIV Gag may differ. Here we analyzed the nucleocytoplasmic transport properties of both Gag proteins. We discovered that inhibition of the CRM1 nuclear export pathway with leptomycin B causes FIV Gag but not HIV-1 Gag to accumulate in the nucleus. Virtually all FIV Gag rapidly became intranuclear when the CRM1 export pathway was blocked, implying that most if not all FIV Gag normally undergoes nuclear cycling. In FIV-infected feline cells, some intranuclear Gag was detected in the steady state without leptomycin B treatment. When expressed individually, the FIV matrix (MA), capsid (CA), and nucleocapsid-p2 (NC-p2) domains were not capable of mediating leptomycin B-sensitive nuclear export of a fluorescent protein. In contrast, CA-NC-p2 did mediate nuclear export, with MA being dispensable. We conclude that HIV-1 and FIV Gag differ strikingly in a key intracellular trafficking property. FIV Gag is a nuclear shuttling protein that utilizes the CRM1 nuclear export pathway, while HIV-1 Gag is excluded from the nucleus. These findings expand the spectrum of lentiviral Gag behaviors and raise the possibility that FIV genome encapsidation may initiate in the nucleus.G ag is both necessary and sufficient for retrovirus particle formation and budding. The protein is translated on free polysomes and targeted to the plasma membrane, where virus particles are assembled (16). A central question is whether Gag and the viral genomic RNA (gRNA) associate at the plasma membrane or earlier during assembly and, if so, whether this occurs in the cytosol; in association with organelles, e.g., cotranslationally; or even in the nucleus, as was described previously for an alpharetrovirus (17). Human immunodeficiency virus type 1 (HIV-1) gRNAs become anchored at the plasma membrane before particle assembly is detectable, but it is not clear whether the Gag-gRNA complexes of this and other lentiviruses first form in the cytoplasm and then transit to the plasma membrane or the gRNA traffics there independently (26,27). Biochemical experiments supported the former scenario, with a monomer or low-order multimers forming on HIV-1 gRNAs and higher-order multimer formation depending on subsequent plasma membrane interactions (33).Gag is encoded by the full-length unspliced viral RNA. To circumvent the cellular checkpoint that prevents the export of intron-containing mRNA, lentiviruses express Rev, which functions as an adaptor between the cellular karyopherin CRM1/exportin-1 and a Rev response element (RRE) located in the 3= region of unspliced viral RNAs (9). However, the main cellular function of the CRM1 nuclear export pathway is the export of cellular proteins containing a...

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Section: Discussionmentioning

confidence: 96%

Feline Immunodeficiency Virus Gag Is a Nuclear Shuttling Protein

Kemler

Saenz

Poeschla

2012

J Virol

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“…Sequence homology of Bud13p to ligands that bind to U2AF-homology motifs of RRM domains suggested that Bud13p interacts with Snu17p according to canonical UHM-ULM interactions (Fig. 6b,d) 13,15,16,[18][19][20][21][22] . However, the three-dimensional structure of the RES core complex demonstrated a distinct interaction mode unlike that of UHM and ULM (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…1a and 2b). In canonical UHM-ULM interactions, the ULM is formed by a positively charged sequence followed by an essential tryptophan [18][19][20][21][22] . In Bud13p the tryptophan is located at position 232, and it was supposed to bind to the hydrophobic pocket between α-helices 1 and 2 (refs.…”

Section: Structure Of the Res Core Complexmentioning

confidence: 99%

Cooperative structure of the heterotrimeric pre-mRNA retention and splicing complex

Wysoczanski

Schneider

Munari

et al. 2014

Nat Struct Mol Biol

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1 1 a r t i c l e sSplicing entails the removal of introns from pre-mRNAs to generate exon-only mRNA, which is exported out of the nucleus for translation 1 . The splicing process is driven and controlled by a large and dynamic RNA-protein complex, the spliceosome 1,2 . The composition and structure of the spliceosome undergoes multiple rearrangements during a splicing reaction, in which a set of distinct structural and compositional states, designated as E, A, B act , B* and C complexes, can be defined 1 . As part of this process, small nuclear ribonucleoprotein (snRNP) particles and non-snRNP splice factors are recruited and released 1,2 . Although the organization of snRNP components of the spliceosome has received considerable attention in recent years, very little is known about the assembly, structure and dynamics of non-snRNP multimeric complexes.The non-snRNP RES complex is present in humans and yeast 3,4 . Deletion of RES genes slows splicing and leads to pre-mRNA leakage into the cytoplasm 3-5 . Distinct introns exhibit RES-dependent splicing 5-9 , as do pre-mRNAs encoding proteins functioning in RNA-nucleotide metabolism 8,10 . Components of the RES complex are found in B and C complexes of the spliceosome, in which RES can interact with U2 snRNP 4,11,12 . In yeast, the RES complex is composed of three proteins, snRNP-associated protein 17 (Snu17p, also known as Ist3p), pre-mRNA-leakage protein 1 (Pml1p) and bud siteselection protein 13 (Bud13p) 3,4 . Snu17p and Bud13p have been implicated directly in splicing 3,5,13 , whereas Pml1p has been linked to the retention of unspliced pre-mRNA in the nucleus 3,5 . Caenorhabditis elegans Bud13p is involved in embryogenesis 14 .Sequence analysis has indicated that Snu17p is a 148-residue (17.1-kDa) noncanonical member of the RRM family of proteins with a long C-terminal part, which exhibits low sequence similarity to published RRM structures 4 . Snu17p binds with nanomolar affinity to the 266-residue (30.5-kDa), natively disordered protein Bud13p 15 . The interaction has been postulated to involve a C-terminal UHM-ligand motif (ULM) in Bud13p that interacts with a U2AF-homology motif (UHM) in the RRM domain of Snu17p 13,15,16 . The only other identified domain encompasses a stretch of lysine residues at the N terminus of Bud13p. Binding of the third component, the 204-residue (23.4-kDa) Pml1p, occurs through its 50 N-terminal disordered residues. The remainder of Pml1p folds as a forkhead-associated domain 13,15,17 , which could potentially bind phosphopeptides 17 . Biochemical evidence has suggested that Snu17p acts as the central binding platform, which interacts with disordered parts of Bud13p and Pml1p 13,15,16 . The precise molecular architecture of the RES complex, however, has been elusive, and its RNA binding capabilities have remained unexplored.Here we solved the three-dimensional structure of the core of the RES complex and demonstrated that its assembly is driven by cooperativity that increases the binding affinity of the components of the complex ...

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“…We identified 22 directed and 121 undirected interactions based on domain-motif and domain-domain interaction predictions, respectively. These interactions were found probable and highly-confident by the ELM structure filter [21] or by the PRINCESS PPI-evaluation tool [22], respectively. For the PRINCESS evaluation we defined a very stringent confidence value at 1000 to filter the total 1427 predicted PPIs to 121 highly-confident interactions.…”

Section: The Nrf2 Interactomementioning

confidence: 99%

The NRF2‐related interactome and regulome contain multifunctional proteins and fine‐tuned autoregulatory loops

et al. 2012

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a b s t r a c t NRF2 is a well-known, master transcription factor (TF) of oxidative and xenobiotic stress responses. Recent studies uncovered an even wider regulatory role of NRF2 influencing carcinogenesis, inflammation and neurodegeneration. Prompted by these advances here we present a systems-level resource for NRF2 interactome and regulome that includes 289 protein-protein, 7469 TF-DNA and 85 miRNA interactions. As systems-level examples of NRF2-related signaling we identified regulatory loops of NRF2 interacting proteins (e.g., JNK1 and CBP) and a fine-tuned regulatory system, where 35 TFs regulated by NRF2 influence 63 miRNAs that down-regulate NRF2. The presented network and the uncovered regulatory loops may facilitate the development of efficient, NRF2-based therapeutic agents.

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ELM--the database of eukaryotic linear motifs

Cited by 308 publications

References 42 publications

Feline Immunodeficiency Virus Gag Is a Nuclear Shuttling Protein

Feline Immunodeficiency Virus Gag Is a Nuclear Shuttling Protein

Cooperative structure of the heterotrimeric pre-mRNA retention and splicing complex

The NRF2‐related interactome and regulome contain multifunctional proteins and fine‐tuned autoregulatory loops

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