Andres Ramos

MRC National Institute for Medical Research, Londinium, England, United Kingdom

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Publications (35)242.56 Total impact

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    ABSTRACT: RNA granules have been observed in different organisms, cell types and under different conditions, and their formation is crucial for the mRNA life cycle. However, very little is known about the molecular mechanisms governing their assembly and disassembly. The aggregation-prone LSCRs (low-sequence-complexity regions), and in particular, the polyQ/N-rich regions, have been extensively studied under pathological conditions due to their role in neurodegenerative diseases. In the present review, we discuss recent in vitro, in vivo and computational data that, globally, suggest a role for polyQ/N regions in RNA granule assembly.
    Biochemical Society Transactions 08/2014; 42(4):1246-50. · 2.59 Impact Factor
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    ABSTRACT: The single-strand-RNA binding protein KSRP is able to negatively regulate gene expression operating with at least two distinct and integrated postranscriptional mechanisms: i) by promoting decay of unstable mRNAs and ii) by favoring maturation from precursors of select microRNAs (miRNAs) including the prototypical tumor suppressor let-7. Studies performed in primary and cultured cells as well as in mice proved that the ability of KSRP to integrate different levels of gene expression is required for proper immune response, lipid metabolism, cell-fate decisions, tissue regeneration, and DNA damage response.
    Seminars in Cell and Developmental Biology 05/2014; · 6.20 Impact Factor
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    ABSTRACT: Regulating the expression of individual miRNAs (microRNAs) is important for cell development and function. The up- or down-regulation of the processing of specific miRNA precursors to the mature active form represents one tool to control miRNA concentration and is mediated by proteins that recognize the terminal loop of the RNA precursors. Terminal loop recognition is achieved by the combined action of several RNA-binding domains. The proteins can then regulate the processing by recruiting RNA enzymes, changing the RNA structure and preventing or enhancing the accessibility and processing activity of the core processing complexes. The present review focuses on how terminal loop-binding proteins recognize their RNA targets and mediate their regulatory function(s), and highlights how terminal loop-mediated regulation relates to the broader regulation of mRNA metabolism.
    Biochemical Society Transactions 08/2013; 41(4):861-5. · 2.59 Impact Factor
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    ABSTRACT: The discovery of effective new antimalarial agents is urgently needed. One of the most frequently-studied molecules anchored to the parasite surface is the merozoite surface protein-1 (MSP1). At red blood cell invasion MSP1 is proteolytically processed and the 19 kDa C-terminal fragment (MSP119) remains on the surface and is taken into the red blood cell, where it is transferred to the food vacuole and persists until the end of the intracellular cycle. Since a number of specific antibodies inhibit erythrocyte invasion and parasite growth, MSP119 is therefore a promising target against malaria. Given the structural homology of cupredoxins with the Fab domain of monoclonal antibodies, an approach combining NMR and ITC measurements with docking calculations based on BiGGER is employed on MSP119-cupredoxin complexes. Among the cupredoxins tested, rusticyanin forms a well-defined complex with MSP119 at a site that overlaps with the surface recognized by the inhibitory antibodies. The addition of holo-rusticyanin to infected cells results in parasitemia inhibition, but negligible effects on parasite growth can be observed for apo-rusticyanin and other proteins of the cupredoxin family. These findings point to rusticyanin as an excellent therapeutic tool for malaria treatment and provide valuable information for drug design.
    Journal of Biological Chemistry 06/2013; 288(29):20896-907. · 4.65 Impact Factor
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    ABSTRACT: KSRP is a single strand nucleic acid binding protein that controls gene expression at multiple levels. In this review we focus on the recent molecular, cellular, and structural insights into the mRNA decay promoting function of KSRP. We discuss also some aspects of KSRP-dependent microRNA maturation from precursors that are related to its mRNA destabilizing function.
    Biochimica et Biophysica Acta 11/2012; · 4.66 Impact Factor
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    ABSTRACT: Let-7 is an important tumor-suppressive microRNA (miRNA) that acts as an on-off switch for cellular differentiation and regulates the expression of a set of human oncogenes. Binding of the human KSRP protein to let-7 miRNA precursors positively regulates their processing to mature let-7, thereby contributing to control of cell proliferation, apoptosis and differentiation. Here we analyze the molecular basis for KSRP-let-7 precursor selectivity and show how the third KH domain of the protein recognizes a G-rich sequence in the pre-let-7 terminal loop and dominates the interaction. The structure of the KH3-RNA complex explains the protein recognition of this noncanonical KH target sequence, and we demonstrate that the specificity of this binding is crucial for the functional interaction between the protein and the miRNA precursor.
    Nature Structural & Molecular Biology 11/2012; · 11.90 Impact Factor
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    ABSTRACT: In eukaryotes, RNA-binding proteins that contain multiple K homology (KH) domains play a key role in coordinating the different steps of RNA synthesis, metabolism and localization. Understanding how the different KH modules participate in the recognition of the RNA targets is necessary to dissect the way these proteins operate. We have designed a KH mutant with impaired RNA-binding capability for general use in exploring the role of individual KH domains in the combinatorial functional recognition of RNA targets. A double mutation in the hallmark GxxG loop (GxxG-to-GDDG) impairs nucleic acid binding without compromising the stability of the domain. We analysed the impact of the GDDG mutations in individual KH domains on the functional properties of KSRP as a prototype of multiple KH domain-containing proteins. We show how the GDDG mutant can be used to directly link biophysical information on the sequence specificity of the different KH domains of KSRP and their role in mRNA recognition and decay. This work defines a general molecular biology tool for the investigation of the function of individual KH domains in nucleic acid binding proteins.
    Nucleic Acids Research 04/2012; 40(14):6873-86. · 8.81 Impact Factor
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    ABSTRACT: microrNNA (mirNAs) are small noncoding RNAs that down-regulate gene expression by reducing stability and/or translation of target mRNAs. In animals, miRNAs arise from sequential processing of hairpin primary transcripts by two rNase III domain-containing enzymes, namely Drosha and Dicer, to generate a mature form of about 22 nucleotides. In this chapter we discuss our latest fndings indicating that KSRP is an integral component of both Drosha and Dicer complexes. KSRP binds to the terminal loop sequence of a subset of miRNA precursors promoting their maturation. our data indicate that the terminal loop is a pivotal structure where activators of miRNA processing as well as repressors of miRNA processing act in a coordinated way to convert cellular signals into changes in miRNA expression processing. This uncovers a new level of complexity of miRNA mechanisms for gene expression regulation.
    07/2011: pages 36-42;
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    Cyprian D Cukier, Andres Ramos
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    ABSTRACT: Here we review the role played by transient interactions between multi-functional proteins and their RNA targets in the regulation of mRNA metabolism, and we describe the important function of NMR spectroscopy in the study of these systems. We place emphasis on a general approach for the study of different features of modular multi-domain recognition that uses well-established NMR techniques and that has provided important advances in the general understanding of post-transcriptional regulation.
    Biophysics of Structure and Mechanism 04/2011; 40(12):1317-25. · 2.44 Impact Factor
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    ABSTRACT: KSRP is a single-strand nucleic acids binding protein that affects RNA fate at multiple levels. KSRP modular structure and its complex pattern of post-translational modifications underpin the interaction with a wide spectrum of RNA target sequences, as well as with other RNA-binding proteins and molecular adaptors. These interactions are important to the regulation of different steps of mRNA metabolism and, in turn, modulate several aspects of cellular proliferation and differentiation. In this review we will discuss in detail KSRP ability to i) promote decay of labile mRNAs interacting with some components of the mRNA decay machinery and ii) favor the maturation of a select group of microRNA precursors.
    Frontiers in Bioscience 01/2011; 16:1787-96. · 3.29 Impact Factor
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    ABSTRACT: KH-type splicing regulatory protein (KSRP)/FBP2, a single-strand nucleic acid binding protein originally identified as both an RNA-binding protein and a transcription factor, affects RNA fates at multiple levels. In this review we will discuss the ability of KSRP to (1) promote decay of labile mRNAs by interacting with some components of the mRNA decay machinery and (2) favor the maturation of a select group of microRNA precursors. We also discuss how its peculiar modular structure allows KSRP to specifically interact with a wide spectrum of RNA sequences and how post-translational modifications influence KSRP functions in cell proliferation and differentiation.
    WIREs RNA 09/2010; 1(2):230-9. · 4.19 Impact Factor
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    ABSTRACT: The far upstream element (FUSE) regulatory system promotes a peak in the concentration of c-Myc during cell cycle. First, the FBP transcriptional activator binds to the FUSE DNA element upstream of the c-myc promoter. Then, FBP recruits its specific repressor (FIR), which acts as an on/off transcriptional switch. Here we describe the molecular basis of FIR recruitment, showing that the tandem RNA recognition motifs of FIR provide a platform for independent FUSE DNA and FBP protein binding and explaining the structural basis of the reversibility of the FBP-FIR interaction. We also show that the physical coupling between FBP and FIR is modulated by a flexible linker positioned sequentially to the recruiting element. Our data explain how the FUSE system precisely regulates c-myc transcription and suggest that a small change in FBP-FIR affinity leads to a substantial effect on c-Myc concentration.
    Nature Structural & Molecular Biology 09/2010; 17(9):1058-64. · 11.90 Impact Factor
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    Alexey L Arkov, Andres Ramos
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    ABSTRACT: The germline originates from primordial embryonic germ cells which give rise to sperm and egg cells and consequently, to the next generation. Germ cells of many organisms contain electron-dense granules that comprise RNA and proteins indispensable for germline development. Here we review recent reports that provide important insights into the structure and function of crucial RNA and protein components of the granules, including DEAD-box helicases, Tudor domain proteins, Piwi/Argonaute proteins and piRNA. Collectively, these components function in translational control, remodeling of ribonucleoprotein complexes and transposon silencing. Furthermore, they interact with each other by means of conserved structural modules and post-translationally modified amino acids. These data suggest a widespread use of several protein motifs in germline development and further our understanding of other ribonucleoprotein structures, for example, processing bodies and neuronal granules.
    Trends in cell biology 08/2010; 20(8):482-90. · 12.12 Impact Factor
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    ABSTRACT: Rna15 is a core subunit of cleavage factor IA (CFIA), an essential transcriptional 3'-end processing factor from Saccharomyces cerevisiae. CFIA is required for polyA site selection/cleavage targeting RNA sequences that surround polyadenylation sites in the 3'-UTR of RNA polymerase-II transcripts. RNA recognition by CFIA is mediated by an RNA recognition motif (RRM) contained in the Rna15 subunit of the complex. We show here that Rna15 has a strong and unexpected preference for GU containing RNAs and reveal the molecular basis for a base selectivity mechanism that accommodates G or U but discriminates against C and A bases. This mode of base selectivity is rather different to that observed in other RRM-RNA structures and is structurally conserved in CstF64, the mammalian counterpart of Rna15. Our observations provide evidence for a highly conserved mechanism of base recognition amongst the 3'-end processing complexes that interact with the U-rich or U/G-rich elements at 3'-end cleavage/polyadenylation sites.
    Nucleic Acids Research 05/2010; 38(9):3119-32. · 8.81 Impact Factor
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    ABSTRACT: KSRP is a multi-domain RNA-binding protein that recruits the exosome-containing mRNA degradation complex to mRNAs coding for cellular proliferation and inflammatory response factors. The selectivity of this mRNA degradation mechanism relies on KSRP recognition of AU-rich elements in the mRNA 3'UTR, that is mediated by KSRP's KH domains. Our structural analysis shows that the inter-domain linker orients the two central KH domains of KSRP-and their RNA-binding surfaces-creating a two-domain unit. We also show that this inter-domain arrangement is important to the interaction with KSRP's RNA targets.
    Nucleic Acids Research 04/2010; 38(15):5193-205. · 8.81 Impact Factor
  • Cyprian D Cukier, Andres Ramos
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    ABSTRACT: The Signal Transduction and Activation of RNA (STAR) protein family regulates different levels of RNA metabolism. STAR proteins have been shown to act as homodimers, and the structure of the QUA1 dimerization region of the GLD-1 protein described in this issue (Beuck et al., 2010) provides a link between homodimerization and the selection of RNA targets.
    Structure 03/2010; 18(3):279-80. · 5.99 Impact Factor
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    ABSTRACT: microRNAs (miRNAs) are small noncodingRNAs that down-regulate gene expression by reducing stability and/or translation of target mRNAs. In animals, miRNAs arise from sequential processing of hairpin primary transcripts by two RNAse III domain-containing enzymes, namely Drosha and Dicer, to generate a mature form of about 22 nucleotides. In this chapter we discuss our latest findings indicating that KSRP is an integral component of both Drosha and Dicer complexes. KSRP binds to the terminal loop sequence of a subset of miRNA precursors promoting their maturation. Our data indicate that the terminal loop is a pivotal structure where activators of miRNA processing as well as repressors of miRNA processing act in a coordinated way to convert cellular signals into changes in miRNA expression processing. This uncovers a new level of complexity of miRNA mechanisms for gene expression regulation.
    Advances in experimental medicine and biology 01/2010; 700:36-42. · 1.83 Impact Factor
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    ABSTRACT: In this point of view we discuss the role of co-activators and co-repressors of miRNA precursors maturation, the possibility that their functions are post translationally regulated by different signaling pathways, and their potential role in the miRNA-dependent control of cell proliferation and differentiation.
    RNA biology 11/2009; 6(5):536-40. · 5.56 Impact Factor
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    ABSTRACT: Consistent with the role of microRNAs (miRNAs) in down-regulating gene expression by reducing the translation and/or stability of target messenger RNAs, the levels of specific miRNAs are important for correct embryonic development and have been linked to several forms of cancer. However, the regulatory mechanisms by which primary miRNAs (pri-miRNAs) are processed first to precursor miRNAs (pre-miRNAs) and then to mature miRNAs by the multiprotein Drosha and Dicer complexes, respectively, remain largely unknown. The KH-type splicing regulatory protein (KSRP, also known as KHSRP) interacts with single-strand AU-rich-element-containing mRNAs and is a key mediator of mRNA decay. Here we show in mammalian cells that KSRP also serves as a component of both Drosha and Dicer complexes and regulates the biogenesis of a subset of miRNAs. KSRP binds with high affinity to the terminal loop of the target miRNA precursors and promotes their maturation. This mechanism is required for specific changes in target mRNA expression that affect specific biological programs, including proliferation, apoptosis and differentiation. These findings reveal an unexpected mechanism that links KSRP to the machinery regulating maturation of a cohort of miRNAs that, in addition to its role in promoting mRNA decay, independently serves to integrate specific regulatory programs of protein expression.
    Nature 06/2009; 459(7249):1010-4. · 38.60 Impact Factor
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    ABSTRACT: The AU-rich element (ARE)-mediated mRNA-degradation activity of the RNA binding K-homology splicing regulator protein (KSRP) is regulated by phosphorylation of a serine within its N-terminal KH domain (KH1). In the cell, phosphorylation promotes the interaction of KSRP and 14-3-3zeta protein and impairs the ability of KSRP to promote the degradation of its RNA targets. Here we examine the molecular details of this mechanism. We report that phosphorylation leads to the unfolding of the structurally atypical and unstable KH1, creating a site for 14-3-3zeta binding. Using this site, 14-3-3zeta discriminates between phosphorylated and unphosphorylated KH1, driving the nuclear localization of KSRP. 14-3-3zeta -KH1 interaction regulates the mRNA-decay activity of KSRP by sequestering the protein in a separate functional pool. This study demonstrates how an mRNA-degradation pathway is connected to extracellular signaling networks through the reversible unfolding of a protein domain.
    Nature Structural & Molecular Biology 03/2009; 16(3):238-46. · 11.90 Impact Factor

Publication Stats

736 Citations
242.56 Total Impact Points

Institutions

  • 2003–2014
    • MRC National Institute for Medical Research
      • Division of Molecular Structure
      Londinium, England, United Kingdom
  • 2013
    • Memorial Sloan-Kettering Cancer Center
      New York City, New York, United States
  • 2012
    • Azienda Ospedaliera Universitaria San Martino di Genova
      Genova, Liguria, Italy
  • 2010–2012
    • Medical Research Council (UK)
      Londinium, England, United Kingdom
    • Murray State University
      • Department of Biological Science
      Murray, KY, United States
  • 2011
    • Karolinska Institutet
      Solna, Stockholm, Sweden
  • 2009–2011
    • Howard Hughes Medical Institute
      Maryland, United States
  • 2005
    • National Chung Hsing University
      • Institute of Biochemistry
      臺中市, Taiwan, Taiwan