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PubMed2006

The multifunctional roles of the four-and-a-half-LIM only protein FHL2.

Numerous cellular processes require the concerted action of multiple proteins that assemble in functional complexes. Protein-protein interaction domains allow specific proteins to combine with certain partners. Specificity of protein-protein association can be obtained by an interaction code predicted by conserved amino acid sequences. One of the protein-protein interaction motifs is the LIM domain, a conserved cysteine-rich module present in more than 100 different human proteins. The human four-and-a-half-LIM-only protein family consists of the members FHL1, FHL2, FHL3, FHL4 and ACT. They are expressed in a cell- and tissue-specific manner and participate in various cellular processes, including regulation of cell survival, transcription and signal transduction. Here, we review the current knowledge of the best-studied member of this family, FHL2. We describe the transcription regulation, the expression profile, the interaction partners, the subcellular localization, the biological functions and discuss the possible involvement of FHL2 in human diseases.

Amino Acid Sequence↗
PubMed2001

The co-chaperone CHIP regulates protein triage decisions mediated by heat-shock proteins.

To maintain quality control in cells, mechanisms distinguish among improperly folded peptides, mature and functional proteins, and proteins to be targeted for degradation. The molecular chaperones, including heat-shock protein Hsp90, have the ability to recognize misfolded proteins and assist in their conversion to a functional conformation. Disruption of Hsp90 heterocomplexes by the Hsp90 inhibitor geldanamycin leads to substrate degradation through the ubiquitin-proteasome pathway, implicating this system in protein triage decisions. We previously identified CHIP (carboxyl terminus of Hsc70-interacting protein) to be an interaction partner of Hsc70 (ref. 4). CHIP also interacts directly with a tetratricopeptide repeat acceptor site of Hsp90, incorporating into Hsp90 heterocomplexes and eliciting release of the regulatory cofactor p23. Here we show that CHIP abolishes the steroid-binding activity and transactivation potential of the glucocorticoid receptor, a well-characterized Hsp90 substrate, even though it has little effect on its synthesis. Instead, CHIP induces ubiquitylation of the glucocorticoid receptor and degradation through the proteasome. By remodelling Hsp90 heterocomplexes to favour substrate degradation, CHIP modulates protein triage decisions that regulate the balance between protein folding and degradation for chaperone substrates.

Animals↗
PubMed2002

The novel human HUEL (C4orf1) protein shares homology with the DNA-binding domain of the XPA DNA repair protein and displays nuclear translocation in a cell cycle-dependent manner.

We have previously isolated and characterized a novel human gene HUEL (C4orf1) that is ubiquitously expressed in a wide range of human fetal, adult tissues and cancer cell lines. HUEL maps to region 4p12-p13 within the short arm of chromosome 4 whose deletion is frequently associated with bladder and other carcinomas. Here we present the genomic organization, sizes and boundaries of exons and introns of HUEL. The GC-rich upstream genomic region and 5' untranslated region (UTR) together constitute a CpG island, a hallmark of housekeeping genes. The 3250 bp HUEL cDNA incorporates a 1704 bp ORF that translates into a hydrophilic protein of 568-amino acids (aa), detected as a band of approximately 70 kDa by Western blotting. We have isolated the murine homolog of HUEL which exhibits 89% nucleotide and 94% amino acid identity to its human counterpart. The HUEL protein shares significant homology with the minimal DNA-binding domain (DNA-BD) of the DNA repair protein encoded by the xeroderma pigmentosum group A (XPA) gene. Other notable features within HUEL include the putative nuclear receptor interaction motif, nuclear localization and export signals, zinc finger, leucine zipper and acidic domains. Mimosine-mediated cell cycle synchronization of PLC/PRF/5 liver cancer cells clearly portrayed translocation of HUEL into the nucleus specifically during the S phase of the cell cycle. Yeast two-hybrid experiments revealed interactions of HUEL with two partner proteins (designated HIPC and HIPB) bearing similarity to a mitotically phosphorylated protein and to reverse transcriptase. Co-immunoprecipitation assays validated the interaction between HUEL and HIPC proteins in mammalian cells. HUEL is likely to be an evolutionarily conserved, housekeeping gene that plays a role intimately linked with cellular replication, DNA synthesis and/or transcriptional regulation.

Active Transport, Cell Nucleus↗
PubMed2003

Alpha(1)-adrenergic receptor subtypes: non-identical triplets with different dancing partners?

Alpha(1)-adrenergic receptors are one of the three subfamilies of G protein coupled receptors activated by epinephrine and norepinephrine to control important functions in many target organs. Three human subtypes (alpha(1A), alpha(1B), alpha(1D)) are derived from separate genes and are highly homologous in their transmembrane domains but not in their amino or carboxyl termini. Recent advances in our understanding of these "non-identical triplets" include development of knockout mice lacking single or multiple subtypes, new insights into subcellular localization and trafficking, identification of allosteric modulators, and increasing evidence for an important role in brain function. Although all three subtypes activate the same G(q/11) signaling pathway, they also appear to interact with different protein binding partners. Recent evidence suggests they may also form dimers, and may initiate independent signals through pathways yet to be clearly elucidated. Thus, this subfamily represents a common phenomenon of a group of similar but non-identical receptor subtypes activated by the same neurotransmitter, whose individual functional roles remain to be clearly established.

Animals↗
PubMed2001

Identification of interaction partners for two closely-related members of the ETS protein family, FLI and ERG.

Fli and erg are two members of the ETS gene family that encodes transcription factors related to the c-ets-1 proto-oncogene. The products of the ETS genes act as transcriptional effectors in cell proliferation, differentiation, and oncogenic transformation. FLI and ERG, two closely-related proteins, bind, as do all the ETS proteins characterized so far, to DNA sequences with an invariable central GGA core flanked by preferred nucleotides. Nevertheless, promoter-specific responses to FLI or ERG may be driven by mechanisms involving multicomponent complexes. Using a yeast two-hybrid screen, we have identified several proteins that physically interact with either FLI or ERG proteins used as bait. The Xenopus developmentally implicated Xvent-2 and Xvent-2B proteins, and the Xenopus splicing factor RNP-C/U1C physically interact with Xl-FLI and Xl-ERG, both in the yeast two-hybrid system and in vitro. We also report the potential interaction of FLI and ERG with Sox-D, a stabilizing protein that may modulate their transcriptional activity. Furthermore, the possible involvement of the transcriptional effectors FLI and ERG in mRNA processing, hematopoiesis or in the control of angiogenesis is suggested through possible interactions with, respectively, RNA binding proteins and hnRNPs, a repressor of the hematopoietic pathway (SAP18), and the HAF protein.

Animals↗
PubMed1999

Comparison of the backbone dynamics of the apo- and holo-carboxy-terminal domain of the biotin carboxyl carrier subunit of Escherichia coli acetyl-CoA carboxylase.

The biotin carboxyl carrier protein (BCCP) is a subunit of acetyl-CoA carboxylase, a biotin-dependent enzyme that catalyzes the first committed step of fatty acid biosynthesis. In its functional cycle, this protein engages in heterologous protein-protein interactions with three distinct partners, depending on its state of post-translational modification. Apo-BCCP interacts specifically with the biotin holoenzyme synthetase, BirA, which results in the post-translational attachment of biotin to a single lysine residue on BCCP. Holo-BCCP then interacts with the biotin carboxylase subunit of acetyl-CoA carboxylase, which leads to the addition of the carboxylate group of bicarbonate to biotin. Finally, the carboxy-biotinylated form of BCCP interacts with transcarboxylase in the transfer of the carboxylate to acetyl-CoA to form malonyl-CoA. The determinants of protein-protein interaction specificity in this system are unknown. The NMR solution structure of the unbiotinylated form of an 87 residue C-terminal domain fragment (residue 70-156) of BCCP (holoBCCP87) and the crystal structure of the biotinylated form of a C-terminal fragment (residue 77-156) of BCCP from Escherichia coli acetyl-CoA carboxylase have previously been determined. Comparative analysis of these structures provided evidence for small, localized conformational changes in the biotin-binding region upon biotinylation of the protein. These structural changes may be important for regulating specific protein-protein interactions. Since the dynamic properties of proteins are correlated with local structural environments, we have determined the relaxation parameters of the backbone 15N nuclear spins of holoBCCP87, and compared these with the data obtained for the apo protein. The results indicate that upon biotinylation, the inherent mobility of the biotin-binding region and the protruding thumb, with which the biotin group interacts in the holo protein, are significantly reduced.

Acetyl-CoA Carboxylase↗
PubMed1998

A Three-dimensional Model of Lanosterol 14alpha-demethylase of Candida albicans.

The three-dimensional structure of lanosterol 14alpha demethylase (P450(14DM), P450(51() of Candida albicans was modeled based on crystallographic coordinates of four prokaryotic cytochrome P450(S): P450BM3, P450cam, P450terp and P450eryF. The sequence of P450(51) was aligned to those of known proteins using a knowledge-based alignment method. The main chain coordinates of the structurally conserved regions (SCRs)) were transferred directly from the corresponding coordinates of P450BM3. The side chain conformations of SCRs) were determined based on the equivalent residues of four crystal structures which had the highest homologous scores. The model was then refined using molecular mechanics and molecular dynamics.The rationale of the resulting model were validated by Ramachandran plot,Profile-3K and hydropathy plot analysis. The structure-functionally important residues, such as the heme binding residues, the residues interacting with redox-partner protein and/or involved in electron transfer, the residues lining substrate access channel and the substrate binding residues, were identified from the model. These residues are candidates for further site-directed mutagensis and site-specific antipeptide antibody binding experiments.

Journal Article↗
PubMed2005

RBR3, a member of the retinoblastoma-related family from maize, is regulated by the RBR1/E2F pathway.

Retinoblastoma-related (RBR) proteins regulate cell division in higher eukaryotes by controlling the adenovirus E2 promoter binding factor (E2F)/dimerization partner (DP) family of transcription factors that regulate expression of many genes involved in cell-cycle progression. We identified a previously undescribed member of the maize RBR family, RBR3, which has the characteristic structure and binding activities of pocket proteins, where interaction depends on a LxCxE motif in the partner proteins and a critical cysteine within the B pocket domain. Like other RBR proteins, RBR3 appears to be regulated by phosphorylation mediated by cyclin-dependent kinases. During endosperm development, RBR3 expression is restricted to the mitotic stage preceding the onset of endoreduplication. This finding suggests a role distinct from RBR1, which is constitutively expressed. Two sites in the RBR3 promoter bind to complexes containing maize E2F1 and DP proteins. Expression of wheat dwarf virus RepA protein, which blocks RBR1 activity and stimulates cell proliferation, dramatically up-regulates RBR3, but not RBR1, RNA in embryogenic maize calli. The results indicate that RBR3 expression is controlled by RBR1 through the activity of E2F/DP and that RBR3 is the maize equivalent of mammalian p107. Furthermore, maize and related grasses might have evolved a compensatory mechanism among distinct types of RBR proteins to ensure robust control of pocket protein activity.

Amino Acid Motifs↗
PubMed2004

Identification of a protein that interacts with the golli-myelin basic protein and with nuclear LIM interactor in the nervous system.

The myelin basic protein (MBP) gene encodes the classic MBPs and the golli proteins, which are related structurally to the MBPs but are not components of the myelin sheath. A yeast two-hybrid approach was used to identify molecular partners that interact with the golli proteins. A mouse cDNA was cloned that encoded a protein of 261 amino acids and called golli-interacting protein (GIP). Database analysis revealed that GIP was the murine homolog of human nuclear LIM interactor-interacting factor (NLI-IF), a nuclear protein whose function is just beginning to be understood. It is a member of a broad family of molecules, found in species ranging from yeast to human, that contain a common domain of approximately 100 amino acids. Immunocytochemical and Northern blot analyses showed co-expression of GIP and golli in several neural cell lines. GIP and golli also showed a similar developmental pattern of mRNA expression in brain, and immunohistochemical staining of GIP and golli showed co-expression in several neuronal populations and in oligodendrocytes in the mouse brain. GIP was localized predominantly in nuclei. GIP co-immunoprecipitated with golli in several in vitro assays as well as from PC12 cells under physiologic conditions. GIP was the first member of this family shown to interact with nuclear LIM interactor (NLI). NLI co-immunoprecipitated with GIP and golli from lysates of N19 cells transfected with NLI, further confirming an interaction between golli, GIP, and NLI. The ability of GIP to interact with both golli and NLI, and the nuclear co-localization of GIP and golli in many cells, indicates a role for the golli products of the MBP gene in NLI- associated regulation of gene expression.

Amino Acid Sequence↗
PubMed2006

Human Dectin-1 isoform E is a cytoplasmic protein and interacts with RanBPM.

Human Dectin-1, a type II transmembrane receptor, is alternatively spliced, generating eight isoforms. Of these isoforms, the isoform E (hDectin-1E) is structurally unique, containing a complete C-type lectin-like domain as well as an ITAM-like sequence. So far, little is known about its function. In the present study, we demonstrated that hDectin-1E was not secreted and it mainly resided in the cytoplasm. Using yeast two-hybrid screening, we identified a Ran-binding protein, RanBPM, as an interacting partner of hDectin-1E. GST pull-down assays showed that RanBPM interacted directly with hDectin-1E and the region containing SPRY domain was sufficient for the interaction. The binding of hDectin-1E and RanBPM was further confirmed in vivo by co-immunoprecipitation assay and confocal microscopic analysis. Taken together, our data provide a clue to the understanding of the function about hDectin-1E.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Differential evolutionary rates of duplicated genes in protein interaction network.

In the network of protein-protein interactions (PPIs), a loss and gain of the partnering proteins can cause drastic changes of network formation during evolution. With the aim of examining the evolutionary effects of the loss and gain of the partnering proteins on PPIs, we examined a relationship between evolutionary rates and losses and/or gains of PPIs for duplicated gene pairs encoding proteins involved in the PPI network. For duplicated pairs, which provided us with a unique opportunity of making fair comparisons of the genes with the same initial condition, we found that the evolutionary rate of the protein with more PPI partners is much slower than that of the other with fewer PPI partners. Moreover, when the ratio of evolutionary rates (faster rate/slower rate) was computed for each of the duplicated pairs, the ratio for the duplicated pair sharing any PPI partners was significantly lower than that for the pair sharing no PPI partners. These results indicate that the duplicated gene pairs differentiate through the losses and/or gains of the PPI partners, resulting in a change in their evolutionary rates. In particular, we point out that the PPI losses for the duplicated gene products that are involved in the functional classes of 'transcription' and 'protein fate' have an impact on their evolutionary rates more than the PPI losses for others.

Biological Evolution↗
PubMed2004

Post-translational modifications in the survival motor neuron protein.

Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by a progressive loss of the spinal motoneurons. The SMA-determining gene has been termed survival motor neuron (SMN) and is deleted or mutated in over 98% of patients. The encoded gene product is a protein expressed as different isoforms. In particular, we showed that the rat SMN cDNA produces two isoforms with M(r) of 32 and 35kDa, both localized in nuclear coiled bodies, but the 32kDa form is also cytoplasmic, whereas the 35kDa form is also microsomal. To determine the molecular relationship between these two isoforms and potential post-translational modifications, we performed transfection experiments with a double-tagged rat SMN. Immunoblot and immunostaining studies demonstrated that the 32kDa SMN isoform derives from the full length 35kDa, through a proteolytic cleavage at the C-terminal. Furthermore, the 35kDa SMN isoform is physiologically phosphorylated in vivo. This may modulate its interaction with molecular partners, either proteins or nucleic acids.

3T3 Cells↗
PubMed1997

Basal transcription factors TBP and TFIIB and the viral coactivator E1A 13S bind with distinct affinities and kinetics to the transactivation domain of NF-kappaB p65.

Transactivation domains (TADs) are able to contact several components of the basal transcription apparatus and co-activator molecules. In order to study these interactions in biophysical detail, binding of the well-characterized TAD from the human transcription factor NF-kappaB p65 (RelA) to the basal transcription factors TBP and TFIIB and the viral co-activator protein E1A 13S was chosen as a model system to investigate the kinetics and affinities of such protein-protein interactions by surface plasmon resonance analysis. The TAD of NF-kappaB p65 showed remarkably different affinities and kinetics in binding to the various proteins. The real-time kinetic measurements revealed an association rate constant (kass) of 2.3 x 10(6)/M/s for the interaction between the p65 TAD and TBP. The association rate constants of the p65 TAD were much weaker for TFIIB (6.8 x 10(4)/M/s) and for the E1A 13S protein (4.9 x 10(4)/M/s). The dissociation rate constants (kdiss) were determined to be 7.9 x 10(-4)/s for TBP, 1.6 x 10(-3)/s for TFIIB and 1.3 x 10(-3)/s for the E1A protein. Accordingly, the calculated dissociation constants (Kd) differed between 3.4 x 10(-10)M for the strongly binding TBP protein and 2.3 x 10(-8)M and 2.6 x 10(-8)M for the weaker binding TFIIB and E1A 13S proteins respectively. Non-linear analysis of the appropriate part of the sensorgrams revealed monophasic association and dissociation kinetics for binding between the p65 TAD and all three interaction partners. The remarkable differences in protein affinities add another aspect to a more detailed understanding of formation of the transcription preinitiation complex. The co-transfection of TBP and E1A 13S stimulated NF-kappaB p65-dependent gene expression, showing the biological significance of these interactions.

Adenovirus E1A Proteins↗
PubMed2005

Geminin regulates neuronal differentiation by antagonizing Brg1 activity.

Precise control of cell proliferation and differentiation is critical for organogenesis. Geminin (Gem) has been proposed to link cell cycle exit and differentiation as a prodifferentiation factor and plays a role in neural cell fate acquisition. Here, we identified the SWI/SNF chromatin-remodeling protein Brg1 as an interacting partner of Gem. Brg1 has been implicated in cell cycle withdrawal and cellular differentiation. Surprisingly, we discovered that Gem antagonizes Brg1 activity during neurogenesis to maintain the undifferentiated cell state. Down-regulation of Gem expression normally precedes neuronal differentiation, and gain- and loss-of-function experiments in Xenopus embryos and mouse P19 cells demonstrated that Gem was essential to prevent premature neurogenesis. Misexpression of Gem also suppressed ectopic neurogenesis driven by Ngn and NeuroD. Gem's activity to block differentiation depended upon its ability to bind Brg1 and could be mediated by Gem's inhibition of proneural basic helix-loop-helix (bHLH)-Brg1 interactions required for bHLH target gene activation. Our data demonstrate a novel mechanism of Gem activity, through regulation of SWI/SNF chromatin-remodeling proteins, and indicate that Gem is an essential regulator of neurogenesis that can control the timing of neural progenitor differentiation and maintain the undifferentiated cell state.

Animals↗
PubMed2000

Tissue-specific splicing of Omi stress-regulated endoprotease leads to an inactive protease with a modified PDZ motif.

Omi is a human serine protease whose catalytic domain is homologous to a bacterial heat shock endoprotease (HtrA), a protein indispensable to the survival of bacteria at elevated temperatures. Omi is expressed ubiquitously, and its protein product is predominantly localized in the endoplasmic reticulum of mammalian cells. Here we present the genomic structure of Omi, consisting of eight exons located on human chromosome 2p12-p13. Furthermore, we describe an alternatively splice form of Omi (D-Omi) that is expressed predominantly in the kidney, colon, and thyroid. D-Omi lacks peptide sequence encoded by two exons (exons III and VII). The absence of exon VII leads to a protein with a modified PDZ domain unable to interact with a known partner, the Mxi2 protein. The absence of exon III affects the catalytic domain and leads to a protein with no detectable protease activity. Our studies suggest that D-Omi may have a unique role in the normal function of kidney, colon, and thyroid.

Amino Acid Sequence↗
PubMed2006

Fission yeast Mcl1 interacts with SCF(Pof3) and is required for centromere formation.

The fission yeast S-phase regulator Mcl1, an orthologue of budding yeast Ctf4, is an interacting protein of DNA polymerase alpha and an important factor to ensure DNA replication and sister chromatid cohesion. Deletion of this protein results in severe cohesion defects, however, the function and cellular role of this protein remains elusive. In this study we isolate Mcl1 as an interaction partner of the F-box protein Pof3, which is a component of the ubiquitin ligase complex SCF(Pof3). Comparing the phenotypes of cells lacking pof3+ or mcl1+ we find a broad overlap including the accumulation of DNA damage and activation of the DNA damage pathway. Importantly, we identity a novel, specific role for Mcl1 in the transcriptional silencing and the localisation of CENP-A at the centromeres.

Centromere↗
PubMed2004

The C terminus of fragile X mental retardation protein interacts with the multi-domain Ran-binding protein in the microtubule-organising centre.

Absence of the fragile X mental retardation protein (FMRP) causes fragile X syndrome, the most common form of hereditary mental retardation. FMRP is a mainly cytoplasmic protein thought to be involved in repression of translation, through a complex network of protein-protein and protein-RNA interactions. Most of the currently known protein partners of FMRP recognise the conserved N terminus of the protein. No interaction has yet been mapped to the highly charged, poorly conserved C terminus, so far thought to be involved in RNA recognition through an RGG motif. In the present study, we show that a two-hybrid bait containing residues 419-632 of human FMRP fishes out a protein that spans the sequence of the Ran-binding protein in the microtubule-organising centre (RanBPM/RanBP9). Specific interaction of RanBPM with FMRP was confirmed by in vivo and in vitro assays. In brain tissue sections, RanBPM is highly expressed in the neurons of cerebral cortex and the cerebellar purkinje cells, in a pattern similar to that described for FMRP. Sequence analysis shows that RanBPM is a multi-domain protein. The interaction with FMRP was mapped in a newly identified CRA motif present in the RanBPM C terminus. Our results suggest that the functional role of RanBPM binding is modulation of the RNA-binding properties of FMRP.

Amino Acid Motifs↗
PubMed2004

The coxsackievirus and adenovirus receptor interacts with the multi-PDZ domain protein-1 (MUPP-1) within the tight junction.

The coxsackievirus and adenovirus receptor (CAR) is a component of the epithelial cell tight junction. In a yeast two-hybrid screen we identified the multi-PDZ domain protein MUPP1 as an interaction partner for the CAR cytoplasmic domain. CAR and MUPP1 were found to colocalize at the tight junction, to coprecipitate from epithelial cells, and to interact in vitro. The interaction was found to specifically involve the PDZ-binding motif within the CAR C terminus and MUPP1 PDZ domain 13. In transfected cells, CAR recruited MUPP1 to cell-cell contacts. The inhibition of CAR expression with small interfering RNA inhibited MUPP1 localization to the tight junction. The results indicated that CAR interacts with MUPP1 and is involved in MUPP1 recruitment to the tight junction.

Animals↗