{"doi":"10.1371/journal.pcbi.1012813","title":"IgStrand: A universal residue numbering scheme for the immunoglobulin-fold (Ig-fold) to study Ig-proteomes and Ig-interactomes","abstract":"<jats:p>\n                    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\n                    <jats:italic>systems</jats:italic>\n                    . 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\n                    <jats:italic>“Ig-fold irreducible structural signature”</jats:italic>\n                    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\n                    <jats:italic>Ig protein folding algorithm</jats:italic>\n                    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.\n                  </jats:p>","journal":"PLOS Computational Biology","year":2025,"id":644809,"datarank":0.29188652235829704,"base_score":1.9459101490553132,"endowment":1.9459101490553132,"self_citation_contribution":0.29188652235829704,"citation_network_contribution":0.0,"self_endowment_contribution":0.29188652235829704,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":609799,"name":"Jiyao Wang","orcid":"0000-0003-3405-240X","position":1,"is_corresponding":false},{"id":1295830,"name":"Umesh Khaniya","orcid":null,"position":2,"is_corresponding":false},{"id":65075,"name":"Thomas Madej","orcid":null,"position":3,"is_corresponding":false},{"id":1453550,"name":"James Song","orcid":"0009-0002-3133-1497","position":4,"is_corresponding":false},{"id":433590,"name":"Ravinder Abrol","orcid":"0000-0001-7333-6793","position":5,"is_corresponding":false},{"id":1608,"name":"Philippe Youkharibache","orcid":"0000-0002-2942-2712","position":6,"is_corresponding":false},{"id":1295829,"name":"Caesar Tawfeeq","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"IgStrand: A universal residue numbering scheme for the immunoglobulin-fold (Ig-fold) to study Ig-proteomes and Ig-interactomes","abstract":"<jats:p>\n                    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\n                    <jats:italic>systems</jats:italic>\n                    . 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\n                    <jats:italic>“Ig-fold irreducible structural signature”</jats:italic>\n                    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\n                    <jats:italic>Ig protein folding algorithm</jats:italic>\n                    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.\n                  </jats:p>","is_dataset_classified":null,"base_score":1.9459101490553132,"endowment":1.9459101490553132,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"40228037","pmcid":"PMC12051499","openalex_id":"https://openalex.org/W4409428540","authors":[],"funders":[{"funder_name":"National Science Foundation","grant_id":"grant 2346274","title":null},{"funder_name":"National Science Foundation","grant_id":"2346274","title":"POSE:  Phase I: Pathway to iCn3D-based Open-Source Ecosystem for Collaborative Research and Education in Mechanistic Biology"},{"funder_name":"NIH","grant_id":"","title":null}],"total_grants":3,"fwci":2.3823,"citation_percentile":0.88246474,"influential_citations":0,"citation_trend":[{"year":2025,"count":3},{"year":2026,"count":3}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://doi.org/10.1371/journal.pcbi.1012813","host_type":"journal"},{"url":"https://doi.org/10.1371/journal.pcbi.1012813","host_type":"publisher"},{"url":"https://dx.plos.org/10.1371/journal.pcbi.1012813","host_type":"publisher"},{"url":"https://pubmed.ncbi.nlm.nih.gov/40228037","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/12051499","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC12051499","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC12051499?pdf=render","host_type":"Europe_PMC"},{"url":"https://doi.org/10.1101/2024.06.10.598201","host_type":""},{"url":"http://dx.doi.org/10.1371/journal.pcbi.1012813","host_type":""}],"fields_of_study":["Glycosylation and Glycoproteins Research","Machine Learning in Bioinformatics","Advanced Proteomics Techniques and Applications","0206 medical engineering","02 engineering and technology","Humans","Proteome","Immunoglobulins","Protein Folding","Computational Biology","Immunoglobulin Domains","Animals","Databases, Protein","Algorithms","Models, Molecular"],"mesh_terms":["Immunoglobulin Domains","Algorithms","Animals","Humans","Immunoglobulins","Models, Molecular","Protein Folding","Computational Biology","Proteome","Databases, Protein"],"keywords":["Proteome","Computational biology","Biology","Numbering","Immunoglobulin domain","Human proteome project","Genome","Proteomics","Genetics","Antibody","Computer science","Gene","Algorithm","Models, Molecular","Protein Folding","Immunoglobulins","Humans","Animals","Immunoglobulin Domains","Databases, Protein","Algorithms","Research Article"],"sdg_mappings":[{"sdg_number":3,"sdg_label":"3. 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