{"doi":"10.1101/2023.01.20.524964","title":"A new Karyopherin-β2 binding PY-NLS epitope of HNRNPH2 is linked to neurodevelopmental disorders","abstract":"Abstract The normally nuclear HNRNPH2 is mutated in HNRNPH2 -related X-linked neurodevelopmental disorder causing the protein to accumulate in the cytoplasm. Interactions of HNRNPH2 with its importin Karyopherin–β2 (Transportin-1) had not been studied. We present a structure that shows Karyopherin-β2 binding HNRNPH2 residues 204-215, a proline-tyrosine nuclear localization signal or PY-NLS that contains a typical R-X 2-4 -P-Y motif, 206 RPGPY 210 , followed a new Karyopherin-β2 binding epitope at 211 DRP 213 that make many interactions with Karyopherin-β2 W373. Mutations at each of these sites decrease Karyopherin-β2 binding affinities by 70-100 fold, explaining aberrant accumulation in cells and emphasizing the role of nuclear import defects in the disease. Sequence/structure analysis suggests that the new epitope C-terminal of the PY-motif, which binds Karyopherin-β2 W373, is rare and thus far limited to close paralogs HNRNPH2, HNRNPH1 and HNRNPF. Karyopherin-β2 W373, a HNRNPH2-binding hotspot, corresponds to W370 of close paralog Transportin-2, a site of pathological variants in patients with neurodevelopmental abnormalities, suggesting that Transportin-2-HNRNPH2/H1/F interactions may be compromised in the abnormalities. Summary HNRNPH2 variants in HNRNPH2 -related X-linked neurodevelopmental disorder aberrantly accumulate in the cytoplasm. A structure of Karyopherin-β2•HNRNPH2 explains nuclear import defects of the variants, reveals a new NLS epitope that suggests mechanistic changes in pathological variants of Karyopherin-β2 paralog Transportin-2.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":398226,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9559,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":283900,"name":"Hong Joo Kim","orcid":"0000-0002-9157-1612","position":1,"is_corresponding":false},{"id":283897,"name":"Brian D. Freibaum","orcid":"0000-0001-5713-2088","position":2,"is_corresponding":false},{"id":841402,"name":"Ho Yee Joyce Fung","orcid":"0000-0002-0502-1957","position":3,"is_corresponding":false},{"id":376060,"name":"Chad A. Brautigam","orcid":"0000-0001-6563-1338","position":4,"is_corresponding":false},{"id":228281,"name":"J. Paul Taylor","orcid":"0000-0002-5794-0349","position":5,"is_corresponding":false},{"id":345462,"name":"Yuh Min Chook","orcid":"0000-0002-4974-0726","position":6,"is_corresponding":false},{"id":677087,"name":"Abner Gonzalez","orcid":"0000-0002-6899-2021","position":0,"is_corresponding":true}],"reference_count":38,"raw_metadata":null,"created_at":"2026-07-19T01:19:43.776284Z","pmid":"36711837","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":[]}