{"doi":"10.1101/2021.07.20.453126","title":"Differences in the dynamics of the tandem-SH2 modules of the Syk and ZAP-70 tyrosine kinases","abstract":"ABSTRACT The catalytic activity of Syk-family tyrosine kinases is regulated by a tandem-SH2 module (tSH2 module). In the autoinhibited state, this module adopts a conformation which stabilizes an inactive conformation of the kinase domain. The binding of the tSH2 module to doubly-phosphorylated tyrosine-containing motifs necessitates a conformational change, thereby relieving kinase inhibition and promoting activation. We determined the crystal structure of the isolated tSH2 module of Syk and find, in contrast to ZAP-70, that its conformation more closely resembles that of the peptide-bound state, rather than the autoinhibited state. Hydrogen-deuterium exchange by mass spectrometry, as well as molecular dynamics simulations, reveal that the dynamics of the tSH2 modules of Syk and ZAP-70 differ, with most of these differences occurring in the C-terminal SH2 domain. Our data suggest that the conformational landscapes of the tSH2 modules in Syk and ZAP-70 have been tuned differently, such that the auto-inhibited conformation of the Syk tSH2 module is less stable. This feature of Syk likely contributes to its ability to more readily escape autoinhibition when compared to ZAP-70, consistent with tighter control of downstream signaling pathways in T cells.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":219142,"datarank":0.16479184330021646,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.0,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9507,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":709738,"name":"Neel H. Shah","orcid":"0000-0002-1186-0626","position":1,"is_corresponding":false},{"id":710609,"name":"Jean M. Badroos","orcid":null,"position":2,"is_corresponding":false},{"id":344885,"name":"Christine L. Gee","orcid":"0000-0002-2632-6418","position":3,"is_corresponding":false},{"id":478687,"name":"Susan Marqusee","orcid":"0000-0001-7648-2163","position":4,"is_corresponding":false},{"id":344888,"name":"John Kuriyan","orcid":"0000-0002-4414-5477","position":5,"is_corresponding":false},{"id":709737,"name":"Helen T. Hobbs","orcid":"0000-0002-4789-0608","position":0,"is_corresponding":true}],"reference_count":30,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:53:33.915158Z","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":[]}