Biology subjects

Youkharibache, P.

Publications and source records attributed to Youkharibache, P..

10 recordsLinked to original sources

bioRxiv2024

Unusual traits shape the architecture of the Ig ancestor molecule

Understanding the ancestral Ig domains molecular structure and tracing the evolution of Ig-like proteins are fundamental components missing from our comprehension of their evolutionary trajectory and function. We have elucidated the molecular structures of two Ig-like proteins from the evolutionary most ancestral phylum, Porifera, revealing previously unidentified Ig-domain features that highlight the concomitant presence of a novel Ig "Early Variable" (EV)-set in tandem with a C1-set domain. The latter, to our knowledge, has never been reported before in non-vertebrates. The IgV and IgC1 sets and their combination into functional Ig-like receptors are part of the adaptive immune system in higher vertebrates, which allows for highly specific immune responses. These observations in the ancient Porifera phylum could indicate the presence of primitive forms of adaptive immunity or a foundational immune strategy that has been conserved through evolution. By unveiling important clues into the molecular configuration of ancestral Ig domains, these findings challenge and expand our understanding of how immunity has evolved within its current landscape.

evolutionary biology↗

bioRxiv2024

A universal residue numbering scheme for the Immunoglobulin-fold (Ig-fold) to study Ig-Proteomes and Ig-Interactomes

The Immunoglobulin fold (Ig-fold) is found in proteins from all domains of life and represents the most populous fold in the human genome, with current estimates ranging from 2 to 3% of protein coding regions. That proportion is much higher in the surfaceome where Ig and Ig-like domains orchestrate cell-cell recognition, adhesion and signaling. The ability of Ig-domains to reliably fold and self-assemble through highly specific interfaces represents a remarkable property of these domains, making them key elements of molecular interaction systems: the immune system, the nervous system, the vascular system and the muscular system. We define a universal residue numbering scheme, common to all domains sharing the Ig-fold in order to study the wide spectrum of Ig-domain variants constituting the Ig-proteome and Ig-Ig interactomes at the heart of these systems. The "IgStrand numbering scheme" enables the identification of Ig structural proteomes and interactomes in and between any species, and comparative structural, functional, and evolutionary analyses. We review how Ig-domains are classified today as topological and structural variants and highlight the "Ig-fold irreducible structural signature" shared by all of them. The IgStrand numbering scheme lays the foundation for the systematic annotation of structural proteomes by detecting and accurately labeling Ig-, Ig-like and Ig-extended domains in proteins, which are poorly annotated in current databases and opens the door to accurate machine learning. Importantly, it sheds light on the robust Ig protein folding algorithm used by nature to form beta sandwich supersecondary structures. The numbering scheme powers an algorithm implemented in the interactive structural analysis software iCn3D to systematically recognize Ig-domains, annotate them and perform detailed analyses comparing any domain sharing the Ig-fold in sequence, topology and structure, regardless of their diverse topologies or origin. The scheme provides a robust fold detection and labeling mechanism that reveals unsuspected structural homologies among protein structures beyond currently identified Ig- and Ig-like domain variants. Indeed, multiple folds classified independently contain a common structural signature, in particular jelly-rolls. Examples of folds that harbor an "Ig-extended" architecture are given. Applications in protein engineering around the Ig-architecture are straightforward based on the universal numbering. AUTHOR SUMMARYThe Immunoglobulin fold (Ig-fold) is a highly conserved protein architecture that has diversified extensively throughout evolution to provide a significant number of Ig-domain types with variable topologies in all life forms. Primarily known for its role in the vertebrate immune system and in particular for its presence in the structure of antibodies, the Ig-domains are found in a myriad of proteins involved in multiple diverse biological/structural functions within the immune, nervous, vascular, and muscular systems, where they mediate neural development, cell-cell recognition, cell adhesion and signaling. Structurally, the Ig-fold consists of 70-110 amino acids that form two beta sheets stabilized by hydrogen bonds facing each other in a sandwich configuration. This architecture provides stability and tremendous adaptability, making the Ig-fold a fundamental building block in many protein families across species, from bacteria to vertebrates. The Ig-fold is most abundant in the human genome, accounting for at least 2-3% of protein-coding regions, which is an underestimate as no reliable method exists to date that can identify all Ig domain variants with precision. To better identify and to study Ig-domain variants and most importantly their specific interactions behind biological functions, the "IgStrand universal residue numbering scheme" was developed. It enables the annotation of the diverse Ig-domain topological variants down to the residue level and their interactions, allowing detailed comparative structural, functional, and evolutionary analyses. This deconstruction of all known Ig-domain topological variant tertiary and quaternary structures will assist in the rational design from scratch of Ig-based therapeutics from single-domain antibodies to cellular therapies against any antigen of interest.

bioinformatics↗

bioRxiv2022

Generation of anti-tumor chimeric antigen receptors incorporating T cell signaling motifs

Chimeric antigen receptors (CAR) T cells have been successfully used to treat lymphoma, leukemia, and multiple myeloma, but adverse effects due to cytokine secretion, CAR-T cell exhaustion, and loss of target antigen have limited their potential. Furthermore, while CARs have been designed to harness T Cell Receptor (TCR) signaling, they are significantly less sensitive than TCRs, resulting in suboptimal signaling. We have developed novel Chimeric Adapter Proteins (CAPs) that are designed to trigger signaling downstream of the TCR{zeta} chain. CAPs are chimeric molecules that contain adapter domains in tandem with the kinase domain of ZAP70, fused to an extracellular targeting domain. We hypothesized that CAPs would be more potent than CARs because kinetic proofreading steps that define the signaling threshold and the inhibitory regulation of upstream molecules are bypassed. Indeed, second generation CAPs exhibited high anti-tumor efficacy, and significantly enhanced long-term in vivo tumor clearance in leukemia-bearing NSG mice as compared with conventional CD19-28{zeta} CAR-T. Mechanistically, CAPs were activated in an Lck-independent manner and displayed slower phosphorylation kinetics and a longer duration of signaling compared with 28{zeta}-CAR. The unique signaling properties of CAPs may therefore be harnessed to improve the in vivo efficacy of T cells engineered to express an anti-tumor chimeric receptor.

immunology↗

bioRxiv2021

iCn3D: from Web-based 3D Viewer to Structure Analysis Tool in Batch Mode

iCn3D was initially developed as a web-based 3D molecular viewer. It then evolved from visualization into a full-featured interactive structural analysis software. It became a collaborative research instrument through the sharing of permanent, shortened URLs that encapsulate not only annotated visual molecular scenes, but also all underlying data and analysis scripts in a FAIR manner. More recently, with the growth of structural databases, the need to analyze large structural datasets systematically led us to use Python scripts and convert the code to be used in Node.js scripts. We showed a few examples of Python scripts at https://github.com/ncbi/icn3d/tree/master/icn3dpython to export secondary structures or PNG images from iCn3D. Users just need to replace the URL in the Python scripts to export other annotations from iCn3D. Furthermore, any interactive iCn3D feature can be converted into a Node.js script to be run in batch mode, enabling an interactive analysis performed on one or a handful of protein complexes to be scaled up to analysis features of large ensembles of structures. Currently available Node.js analysis scripts examples are available at https://github.com/ncbi/icn3d/tree/master/icn3dnode. This development will enable ensemble analyses on growing structural databases such as AlphaFold or RoseTTAFold on one hand and Electron Microscopy on the other. In this paper, we also review new features such as DelPhi electrostatic potential, 3D view of mutations, alignment of multiple chains, assembly of multiple structures by realignment, dynamic symmetry calculation, 2D cartoons at different levels, interactive contact maps, and use of iCn3D in Jupyter Notebook as described at https://pypi.org/project/icn3dpy.

bioinformatics↗

bioRxiv2021

Topological and Structural Plasticity of the single Ig fold and the double Ig fold present in CD19

The Ig-fold has had a remarkable success in vertebrate evolution, with a presence in over 2% of human genes. The Ig-fold is not just the elementary structural domain of antibodies and TCRs, it is also at the heart of a staggering 30% of immunologic cell surface receptors, making it a major orchestrator of cell-cell-interactions. While BCRs, TCRs, and numerous Ig-based cell surface receptors form homo or heterodimers on the same cell surface (in cis), many of them interface as ligand-receptors (checkpoints) on interacting cells (in trans) through their Ig domains. New Ig-Ig interfaces are still being discovered between Ig-based cell surface receptors, even in well known families such as B7. What is largely ignored however is that the Ig-fold itself is pseudo-symmetric, a property that makes the Ig-domain a versatile self-associative 3D structure and may in part explain its success in evolution, especially through its ability to bind in cis or in trans in the context of cell surface receptor-ligand interactions. In this paper we review the Ig domains tertiary and quaternary pseudo symmetries, with a particular attention to the newly identified double Ig fold in the solved CD19 molecular structure to highlight the underlying fundamental folding elements of Ig domains, i.e. Ig protodomains. This pseudosymmetric property of Ig domains gives us a decoding frame of reference to understand the fold, relate all Ig-domain forms, single or double, and suggest new protein engineering avenues.

immunology↗

bioRxiv2020

Using iCn3D and the World Wide Web for structure-based collaborative research: Analyzing molecular interactions at the root of COVID-19

ABSTRACTThe COVID-19 pandemic took us ill-prepared and tackling the many challenges it poses in a timely manner requires world-wide collaboration. Our ability to study the SARS-COV-2 virus and its interactions with its human host in molecular terms efficiently and collaboratively becomes indispensable and mission-critical in the race to develop vaccines, drugs, and neutralizing antibodies. There is already a significant corpus of 3D structures related to SARS and MERS coronaviruses, and the rapid generation of new structures demands the use of efficient tools to expedite the sharing of structural analyses and molecular designs and convey them in their native 3D context in sync with sequence data and annotations. We developed iCn3D (pronounced “I see in 3D”) 1 to take full advantage of web technologies and allow scientists of different backgrounds to perform and share sequence-structure analyses over the Internet and engage in collaborations through a simple mechanism of exchanging “lifelong” web links (URLs). This approach solves the very old problem of “sharing of molecular scenes” in a reliable and convenient manner. iCn3D links are sharable over the Internet and make data and entire analyses findable, accessible, and reproducible, with various levels of interoperability. Links and underlying data are FAIR 2 and can be embedded in preprints and papers, bringing a 3D live and interactive dimension to a world of text and static images used in current publications, eliminating at the same time the need for arcane supplemental materials. This paper exemplifies iCn3D capabilities in visualization, analysis, and sharing of COVID-19 related structures, sequence variability, and molecular interactions.Competing Interest StatementThe authors have declared no competing interest.View Full Text

bioinformatics↗

bioRxiv2018

iCn3D, a Web-based 3D Viewer for the Visualization of Biomolecular Structure and Sequence Annotation

SummaryiCn3D (l-see-in-3D) is a web-based 3D molecular structure viewer implemented in JavaScript. It invites users to explore sequence-structure relationships by displaying 3D structures, protein and nucleotide sequences, and biological annotations such as protein domains, Single Nucleotide Variations, functional sites, molecular contacts, as well as user defined features. Customized and user-annotated displays can be shared with colleagues or publishers via a simple URL, or embedded in web pages as live 3D displays. iCn3D is unique in its ability to simultaneously show 3D structure, 2D molecular networks and interactions, and 1D protein and nucleotide sequences through an integrated sequence/annotation browser. Arbitrary molecular features can be selected in any of the 1D/2D/3D windows as sets of molecules or residues, utilizing flexible user interfaces. These selections are synchronized dynamically in all displays. They can, for example, be shown as tracks in the 1D sequence/annotation browser with simultaneous 3D representations. They can be saved and reused throughout a single user session, or exported for subsequent sessions and further external analysis. iCn3D is rich in structural analysis and visualization features and has a built-in user interface that supports both command line- and menu-driven operation. Session commands can be saved, replayed and shared. iCn3D can display superimposed structures obtained from NCBFs VAST+ structural alignment resource, for comparative analysis of tertiary or quaternary structure. iCn3D can also display electron density maps for crystal structures and export files for 3D printing. The following example URL exemplifies some of the 1D/2D/3D representations: https://www.ncbi.nlm.nih.gov/Structure/icn3d/full.html?mmdbid=1TUP&showanno=1&show2d=1&showsets=1.\n\nAvailability and implementationiCn3D is freely available to the public. Its source code is available at https://github.com/ncbi/icn3d.

bioinformatics↗

bioRxiv2018

Pseudo-Symmetry and Conformational Plasticity in 7 Transmembrane Helix (7TMH) Proteins: Intragenic Duplication and Assembly of 3TMH or 4TMH Protodomains with Evolutionary Balance of Structural Constraints and Functional Divergence

Membrane proteins sharing 7 transmembrane helices (7-TMH) dominate the polytopic TMH proteome. They cannot be grouped under a monolithic fold or superfold, however, a parallel structural analysis of folds around that magic number of 7-TMH in distinct 6/7/8-TMH protein superfamilies (SWEET, PnuC, TRIC, FocA, Aquaporin, GPCRs, AND MFS), reveals a common homology, not in their structural fold, but in their systematic pseudo-symmetric construction. Our analysis leads to guiding principles of intragenic duplication and pseudo-symmetric assembly of ancestral 3 or 4 Transmembrane Helix (3/4-TMH) protodomains/protofolds. A parallel deconstruction and reconstruction of these domains provides a structural and mechanistic framework for the evolution path of current pseudo-symmetrical transmembrane helical (TMH) proteins. It highlights the conformational plasticity inherent to fold formation itself. The sequence/structure analysis of different 6/7/8-TMH superfamilies provides a unifying theme of their evolutionary process involving the intragenic duplication of protodomains with varying degrees of sequence and fold divergence under conformational and functional constraints.

bioinformatics↗

bioRxiv2017

Twelve Elements of Visualization and Analysis for Tertiary and Quaternary Structure of Biological Molecules

During the last decades, 3D Molecular Graphics in Life Sciences has been used almost exclusively by experts through complex software and applications ranging from Structural Biology to Computer Aided Drug Design. The emergence of JavaScript and WebGL as a viable platform has enabled 3D visualization of biomolecular structures through Web browsers, without any need for specialized software. Although still in its infancy, Web Molecular Graphics opens new perspectives. This white paper, proposes a set of Twelve Elements to consider to enable 3D visualization and structural analyses of biological systems in Web molecular viewers. The Elements go beyond 3D graphics and propose an integrated approach to visualize and analyze molecular entities and their interactions in multiple dimensions, at multiple levels of details, for diverse users. The bridging of 1D sequence browsers and 3D structure viewers, possible under a Web browser, enables information flow where molecular biologists can use structural information directly at the sequence level. Given the tsunami of sequence information linked to diseases from next generation sequencing - in need for interpretation - making structural information readily available to research scientists is a tremendous opportunity for medical discovery. The Twelve Elements are conceptual and are intended to entice developers to architect software components and APIs, and to gather together as a community around common goals and open source software. A few features of emerging viewers, all available as open source, are highlighted. Speed and quality of 3D graphics for large molecular systems, the interoperability of Web components, and the instantaneous sharing of annotated visualizations through the Web, are some of the most amazing and promising capabilities of 3D Web viewing, opening bright perspectives for Life Sciences research.

bioinformatics↗

bioRxiv2017

The Structure Of Small Beta Barrels

0.The small {beta}-barrel is an ancient protein structural domain characterized by extremes: It features an extremely broad range of structural varieties, a deeply intricate evolutionary history, and it is associated with a bewildering array of biomolecular pathways and physiological functions. These and related features of this domain are described and analyzed herein. Specifically, we present a comprehensive, survey-based analysis of the structural properties of small {beta}-barrels (SBBs). We first consider the defining characteristics of the SBB fold, as well as the various systems of nomenclature used to describe it. In order to begin elucidating how such vast functional diversity is achieved by a relatively simple protein domain, we then explore the anatomy of the SBB fold and some of its representative structural variants. Many types of SBB proteins assemble into cyclic oligomers that act as the biologically-functional entity. These oligomers exhibit a great deal of plasticity even at the quaternary structural level--including homomeric and heteromeric assemblies, rings of variable subunit stoichiometries (pentamer, hexamer, etc.), as well as higher-order oligomers (e.g., double-rings) and fibrillar polymers. We conclude with three themes that emerge from the SBBs unique structure{leftrightarrow}function versatility.

bioinformatics↗