{"doi":"10.1073/pnas.0801207105","title":"Built-in loops allow versatility in domain–domain interactions: Lessons from self-interacting domains","abstract":"<jats:p>Compilations of domain–domain interactions based on solved structures suggest there are distinct domain pairs that are used repeatedly in different protein contexts to mediate protein–protein interactions. However, not all protein pairs with the corresponding domains that can potentially mediate interaction do interact, even when they are colocalized and coexpressed. It is conceivable that there are structural and sequence features, below the domain level, that play a role in determining the potential of domains to mediate protein–protein interactions. Here, we discover such features by comparing domains that, on the one hand, mediate homodimerization of proteins and, on the other, occur in different proteins that are documented as monomers. Intriguingly, this comparison uncovered surface loops that can be considered as determinants of the interactions. There are enabling loops, which mediate the domain interactions, and disabling loops that prevent the interactions. The presence of the enabling/disabling loops is consistent with the fulfillment/prevention of the interaction and is highly preserved in evolution. This suggests that, along with the preservation of structural elements that enable interaction, evolution maintains elements intended to prevent unwanted interactions. The enabling and disabling loops discovered in this study have implications in prediction of protein–protein interactions, by pointing to the protein regions that determine the interaction. Our results extend the hierarchy of attributes that collectively establish the modularity of domain-mediated protein–protein interactions.</jats:p>","journal":"Proceedings of the National Academy of Sciences","year":2008,"id":657007,"datarank":0.6966586348712059,"base_score":4.6443908991413725,"endowment":4.6443908991413725,"self_citation_contribution":0.6966586348712059,"citation_network_contribution":0.0,"self_endowment_contribution":0.6966586348712059,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":103,"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":1715016,"name":"Zohar Itzhaki","orcid":null,"position":1,"is_corresponding":false},{"id":34443,"name":"Hanah Margalit","orcid":"0000-0002-2274-7784","position":2,"is_corresponding":false},{"id":563702,"name":"Eyal Akiva","orcid":"0000-0001-6074-8609","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Built-in loops allow versatility in domain–domain interactions: Lessons from self-interacting domains","abstract":"<jats:p>Compilations of domain–domain interactions based on solved structures suggest there are distinct domain pairs that are used repeatedly in different protein contexts to mediate protein–protein interactions. However, not all protein pairs with the corresponding domains that can potentially mediate interaction do interact, even when they are colocalized and coexpressed. It is conceivable that there are structural and sequence features, below the domain level, that play a role in determining the potential of domains to mediate protein–protein interactions. Here, we discover such features by comparing domains that, on the one hand, mediate homodimerization of proteins and, on the other, occur in different proteins that are documented as monomers. Intriguingly, this comparison uncovered surface loops that can be considered as determinants of the interactions. There are enabling loops, which mediate the domain interactions, and disabling loops that prevent the interactions. The presence of the enabling/disabling loops is consistent with the fulfillment/prevention of the interaction and is highly preserved in evolution. This suggests that, along with the preservation of structural elements that enable interaction, evolution maintains elements intended to prevent unwanted interactions. The enabling and disabling loops discovered in this study have implications in prediction of protein–protein interactions, by pointing to the protein regions that determine the interaction. Our results extend the hierarchy of attributes that collectively establish the modularity of domain-mediated protein–protein interactions.</jats:p>","is_dataset_classified":null,"base_score":4.6443908991413725,"endowment":4.6443908991413725,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"18757736","pmcid":"PMC2533183","openalex_id":"https://openalex.org/W1973695911","authors":[],"funders":[],"total_grants":0,"fwci":3.0561,"citation_percentile":0.91418528,"influential_citations":0,"citation_trend":[{"year":2012,"count":11},{"year":2013,"count":8},{"year":2014,"count":3},{"year":2015,"count":4},{"year":2016,"count":9},{"year":2017,"count":6},{"year":2018,"count":8},{"year":2019,"count":7},{"year":2020,"count":5},{"year":2021,"count":8},{"year":2022,"count":6},{"year":2023,"count":1},{"year":2025,"count":4},{"year":2026,"count":1}],"oa_status":"green","license":null,"oa_locations":[{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/2533183","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/2533183","host_type":"repository"},{"url":"https://pnas.org/doi/pdf/10.1073/pnas.0801207105","host_type":"publisher"},{"url":"https://doi.org/10.1073/pnas.0801207105","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/18757736","host_type":"repository"}],"fields_of_study":["Protein Structure and Dynamics","Microbial Metabolic Engineering and Bioproduction","Bioinformatics and Genomic Networks","Amino Acid Sequence","Animals","Computational Biology","Humans","Molecular Sequence Data","Protein Binding","Protein Interaction Domains and Motifs","Proteins"],"mesh_terms":["Amino Acid Sequence","Animals","Humans","Molecular Sequence Data","Protein Binding","Proteins","Computational Biology","Protein Interaction Domains and Motifs"],"keywords":["Protein–protein interaction","Domain (mathematical analysis)","Modularity (biology)","Protein domain","Hierarchy","Computational biology","Protein structure","Biology","Signaling proteins","Computer science","Genetics","Biochemistry","Signal transduction","Gene"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"pdb"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-11T23:15:41.107037Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}