Deletion analysis defines distinct functional domains for protein-protein and nucleic acid interactions in the ORF1 protein of mouse LINE-1 1 1Edited by J. Karn

Martin, Sandra L.; Li, Jinfang; Weisz, Julie A.

doi:10.1006/jmbi.2000.4182

Cited by 66 publications

(70 citation statements)

References 19 publications

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“…An analysis of its primary sequence using the program MULTICOIL predicts that residues 63-130 form a coiled-coil with a confidence level that exceeds 50% with a 21-residue prediction window. This is compatible with studies that have shown that this region contains determinants required for oligomerization (26,28,64). At the Nand C-terminal ends of the C-C fragment, 18 and 39 amino acids surround the predicted coiled-coil, respectively.…”

Section: Discussionsupporting

confidence: 90%

“…Sedimentation and atomic force microscopy (AFM) studies indicate that it is a dumbbell-shaped homotrimer that is presumably held together by a trimeric coiled-coil (26). Residues at the C-terminal end of ORF1p show the greatest degree of sequence conservation and bind and chaperone nucleic acids (27,28). In this report, limited proteolysis has been used to identify three distinct domains: the coiled-coil, middle, and C-terminal domains.…”

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confidence: 99%

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Identification and Solution Structure of a Highly Conserved C-terminal Domain within ORF1p Required for Retrotransposition of Long Interspersed Nuclear Element-1

Januszyk

Villareal

et al. 2007

Journal of Biological Chemistry

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Long interspersed nuclear element-1 (LINE-1 or L1) retrotransposons comprise a large fraction of the human and mouse genomes. The mobility of these successful elements requires the protein encoded by open reading frame-1 (ORF1p), which binds single-stranded RNA with high affinity and functions as a nucleic acid chaperone. In this report, we have used limited proteolysis, filter binding, and NMR spectroscopy to characterize the global structure of ORF1p and the three-dimensional structure of a highly conserved RNA binding domain. ORF1p contains three structured regions, a coiled-coil domain, a middle domain of unknown function, and a C-terminal domain (CTD). We show that high affinity RNA binding by ORF1p requires the CTD and residues within an amino acid protease-sensitive segment that joins the CTD to the middle domain. Insights in the mechanism of RNA binding were obtained by determining the solution structure of the CTD, which is shown to adopt a novel fold consisting of a three-stranded ␤ sheet that is packed against three ␣-helices. An RNA binding surface on the CTD has been localized using chemical shift perturbation experiments and is proximal to residues previously shown to be essential for retrotransposition, RNA binding, and chaperone activity. A similar structure and mechanism of RNA binding is expected for all vertebrate long interspersed nuclear element-1 elements, since residues encoding the middle, protease-sensitive segment, and CTD are highly conserved.

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Section: Discussionsupporting

confidence: 90%

mentioning

confidence: 99%

Identification and Solution Structure of a Highly Conserved C-terminal Domain within ORF1p Required for Retrotransposition of Long Interspersed Nuclear Element-1

Januszyk

Villareal

et al. 2007

Journal of Biological Chemistry

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“…Consistent with such nucleic acid chaperone activity (25,31,43,45), we observe that the monomeric RRM-CTD fragment binds nucleic acids as single strands, but does not prevent them from forming base-paired structures that cannot be bound anymore. On the molecular level this could be achieved by an interaction mainly with the flexible phosphate-ribose backbone of a single-stranded nucleic acid, leaving the bases exposed for interactions.…”

Section: Identification Of Rrm Domains In Nlrs and Their Significancesupporting

confidence: 71%

“…S2). This represents a significantly larger portion of the protein as compared with previous studies with the murine protein (23,24,43). Furthermore, we can show that the predicted RRM-and CTD domains (hL1ORF1p-M and hL1ORF1p-C, respectively) are soluble independently from each other and remain monomeric at concentrations up to 100 M. When mixed at these concentrations, they also do not detectably interact with each other (see Fig.…”

Section: Orf1pmentioning

confidence: 52%

“…The present identification of the RRM domain in human L1ORF1p leads to a redefinition of L1ORF1p structure and is in conflict with previous reports, which assumed an unstructured linker in the center of the protein. The significance of results obtained with protein constructs that contain less than half of the RRM domain therefore needs to be revisited, as we do not expect the RRM domain to get folded in this context (23,24,43).…”

Section: Domain Structure and Nucleic Acid Binding Of Human L1orf1pmentioning

confidence: 99%

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Non-LTR retrotransposons encode noncanonical RRM domains in their first open reading frame

Khazina

Weichenrieder

2009

Proc. Natl. Acad. Sci. U.S.A.

135

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Non-LTR retrotransposons (NLRs) are a unique class of mobile genetic elements that have significant impact on the evolution of eukaryotic genomes. However, the molecular details and functions of their encoded proteins, in particular of the accessory ORF1p proteins, are poorly understood. Here, we identify noncanonical RNA-recognitionmotifs (RRMs) in several phylogenetically unrelated NLR ORF1p proteins. This provides an explanation for their RNA-binding properties and clearly shows that they are not related to the retroviral nucleocapsid protein Gag, despite the frequent presence of CCHC zinc knuckles. In particular, we characterize the ORF1p protein of the human long interspersed nuclear element 1 (LINE-1 or L1). We show that L1ORF1p is a multidomain protein, consisting of a coiled coil (cc), RRM, and C-terminal domain (CTD). Most importantly, we solved the crystal structure of the RRM domain, which is characterized by extended loops stabilized by unique salt bridges. Furthermore, we demonstrate that L1ORF1p trimerizes via its N-terminal cc domain, and we suggest that this property is functionally important for all homologues. The formation of distinct complexes with singlestranded nucleic acids requires the presence of the RRM and CTD domains on the same polypeptide chain as well as their close cooperation. Finally, the phylogenetic analysis of mammalian L1ORF1p shows an ancient origin of the RRM domain and supports a modular evolution of NLRs.genome evolution ͉ LINE-1 ͉ nucleic acid chaperone ͉ RNP ͉ crystal structure

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Progress in understanding the biology of the human mutagen LINE-1

2007

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Long interspersed nucleotide element (LINE)-1 retrotransposon (L1) has emerged as the largest contributor to mammalian genome mass, responsible for over 35% of the human genome. Differences in the number and activity levels of L1s contribute to interindividual variation in humans, both by affecting an individual's likelihood of acquiring new L1-mediated mutations, as well as by differentially modifying gene expression. Here, we report on recent progress in understanding L1 biology, with a focus on mechanisms of L1-mediated disease. We discuss known details of L1 life cycle, including L1 structure, transcriptional regulation, and the mechanisms of translation and retrotransposition. Current views on cell type specificity, timing, and control of retrotransposition are put forth. Finally, we discuss the role of L1 as a mutagen, using the latest findings in L1 biology to illuminate molecular mechanisms of L1-mediated gene disruption.

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Deletion analysis defines distinct functional domains for protein-protein and nucleic acid interactions in the ORF1 protein of mouse LINE-1 1 1Edited by J. Karn

Cited by 66 publications

References 19 publications

Identification and Solution Structure of a Highly Conserved C-terminal Domain within ORF1p Required for Retrotransposition of Long Interspersed Nuclear Element-1

Identification and Solution Structure of a Highly Conserved C-terminal Domain within ORF1p Required for Retrotransposition of Long Interspersed Nuclear Element-1

Non-LTR retrotransposons encode noncanonical RRM domains in their first open reading frame

Progress in understanding the biology of the human mutagen LINE-1

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