Sequence motif

Résumé

In biology, a sequence motif is a nucleotide or amino-acid sequence pattern that is widespread and usually assumed to be related to biological function of the macromolecule. For example, an N-glycosylation site motif can be defined as Asn, followed by anything but Pro, followed by either Ser or Thr, followed by anything but Pro residue. Overview When a sequence motif appears in the exon of a gene, it may encode the "structural motif" of a protein; that is a stereotypical element of the overall structure of the protein. Nevertheless, motifs need not be associated with a distinctive secondary structure. "Noncoding" sequences are not translated into proteins, and nucleic acids with such motifs need not deviate from the typical shape (e.g. the "B-form" DNA double helix). Outside of gene exons, there exist regulatory sequence motifs and motifs within the "junk", such as satellite DNA. Some of these are believed to affect the shape of nucleic acids (see for example RNA self-spl

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https://en.wikipedia.org/wiki/Sequence_motif

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Despite decades of research in Alzheimerâs disease (AD), no treatment has been found to efficiently prevent or cure its progression. The microtubule binding protein Tau plays central roles in the pathogenesis of AD and is found, in the form of paired helical filaments (PHFs), as the main component of the neurofibrillary tangles, a major pathological hallmark of AD. Therefore, a better understanding of the molecular and structural determinants of Tau normal and pathological functions is crucial to elucidate the role of Tau in AD. The work presented in this thesis represents our efforts to contribute to addressing this knowledge gap by investigating the sequence, molecular and structural determinants of Tau aggregation, membrane binding, and toxicity and by exploring the interplay between these different properties. In Chapter 1, we assess the effect of manipulating the aggregation conditions on the fibril polymorphism of 4R Tau, the K18 fragment and the four individual repeat peptides within the microtubule binding domain, namely R1, R2, R3 and R4. The fibrilar structures formed by Tau, K18, R2 and R3 are diverse, polymorphic and depend upon the aggregation conditions. This work paves the way to a better understanding of molecular basis underlying Tau fibrils formation and demonstrates the importance of interplay between the different sequence motifs in Tau. In Chapter 2, we describe the discovery of a Tau-derived peptide that forms fibrils with a unique capacity to seed the aggregation of full-length Tau and templates its aggregation into highly ordered twisted fibrils that resemble native PHFs. This has tremendous potential applications in the understanding the biophysical properties of the PHFs, but also provide a powerful platform for designing Tau-specific imaging probes or the screening for small molecule modulators of fibrillization and clearance. In Chapter 3, we investigate the sequence determinants and structural consequences of the interactions of Tau with membranes, and describe for the first time the formation of stable protein/lipid complexes. Using NMR, we determined that the core of these complexes is comprised of short motifs localized in R2 and R3. We designed novel mutants that disrupt Tau interactions with lipids, thus providing powerful tools for investigating the role of membrane interactions in regulating the functions of Tau. Our findings point toward a novel form of Tau complexes that might be part of a membrane-dependent mechanism that regulates Tau oligomerization and toxicity. In Chapter 4, we explore the effect of tyrosine phosphorylation in regulating Tau properties. We report that phosphorylation at Y310, which is located within R3, results in the greatest inhibition of Tau fibril formation. We also identified two novel Tau kinases, Fes and Btk that phosphorylate Tau at positions Y310 and Y394, and developed antibodies specific for pY310 and pY394, thereby providing novel targets and tools that could lead to the discovery of novel mechanisms and pathways involved in regulating Tau functions. In addition to providing several tools to allow further understanding of Tau functions and implications in AD, our work underscores the importance of investigating the individual domains of Tau, especially R2 and R3, as structural determinant of Tau self-assembly and binding to membranes and demonstrates the critical involvement of phosphorylation of the Y310 residue in Tau biophysical and cellular properties.

EPFL2017

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The human CC chemokine receptor 5 (CCR5) is a G protein-coupled receptor (GPCR) that plays a major role in inflammation and is involved in cancer, HIV, and COVID-19. Despite its importance as a drug target, the molecular activation mechanism of CCR5, i.e., how chemokine agonists transduce the activation signal through the receptor, is yet unknown. Here, we report the cryo-EM structure of wild-type CCR5 in an active conformation bound to the chemokine super-agonist [6P4]CCL5 and the heterotrimeric Gi protein. The structure provides the rationale for the sequence-activity relation of agonist and antagonist chemokines. The N terminus of agonist chemokines pushes onto specific structural motifs at the bottom of the orthosteric pocket that activate the canonical GPCR microswitch network. This activation mechanism differs substantially from other CC chemokine receptors that bind chemokines with shorter N termini in a shallow binding mode involving unique sequence signatures and a specialized activation mechanism.

AMER ASSOC ADVANCEMENT SCIENCE2021

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A variety of DNA-binding proteins organizes the chromosomal DNA and regulates gene transcription, and DNA replication and recombination. In particular, for gene regulation there is a category of DNA-binding proteins, the transcription factors, which can detect and bind to a specific set of DNA motifs. For the protein-DNA complexes there are some solved structures, but for some cases, it is difficult to define experimentally these structures at the atomistic level. However, there are various in silico methods, that alone or in combination with experimental techniques, are capable of predicting proteins structures with high accuracy. DNA-binding proteins contain DNA-binding domains and unfortunately, there are few protein-DNA complexes that have been characterized at atomistic resolution. Here we have developed artificial neural networks to predict the binding sites and the interface between proteins and the DNA, based on a structure-based approach. Specifically, we used different interface descriptors and we included a variety of protein-DNA complexes, in order to predict the correct localizations of the DNA on a protein. A large group of proteins that can recognize specific DNA sequences is the KRAB-ZFP family. DNA recognition by zinc finger proteins (ZFPs) plays an important role in gene regulation. However, the molecular determinants defining the recognition of specific DNA nucleotides by ZFP finger repeats has not yet been decoded. Here, we present a method that can predict which ZF repeats specifically bind to a DNA target sequence and what is the most probable DNA target sequence for these repeats. Our method is based on the structural analysis of the binding network of resolved protein DNA complexes, and is validated on a benchmark set of solved ZFP-DNA complexes. We also characterized the binding specificity of two KRAB-ZFPs (ZFP14 and ZNF145) integrating our predictions with SMiLE-seq (Selective Microfluidics-based Ligand Enrichment followed by sequencing) data. Subsequently, we use our recognition code on ChIP-exo data, in order to give an insight into the poly-ZF domains binding patterns. We determined the most probable binding motifs and we separated the ZFPs in two groups: the ones that have a potential canonical and non-canonical binding. Altogether, this work gives an insight into the proteins that interact with the DNA, through a better understanding of the various protein-DNA interfaces and the predictions of these complexes at the atomistic level.

EPFL2019

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EPFL2017

EPFL2019