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TitleA new Karyopherin-β2 binding PY-NLS epitope of HNRNPH2 linked to neurodevelopmental disorders.
Journal, issue, pagesStructure, Vol. 31, Issue 8, Page 924-934.e4, Year 2023
Publish dateAug 3, 2023
AuthorsAbner Gonzalez / Hong Joo Kim / Brian D Freibaum / Ho Yee Joyce Fung / Chad A Brautigam / J Paul Taylor / Yuh Min Chook /
PubMed AbstractThe HNRNPH2 proline-tyrosine nuclear localization signal (PY-NLS) is mutated in HNRNPH2-related X-linked neurodevelopmental disorder, causing the normally nuclear HNRNPH2 to accumulate in the ...The HNRNPH2 proline-tyrosine nuclear localization signal (PY-NLS) is mutated in HNRNPH2-related X-linked neurodevelopmental disorder, causing the normally nuclear HNRNPH2 to accumulate in the cytoplasm. We solved the cryoelectron microscopy (cryo-EM) structure of Karyopherin-β2/Transportin-1 bound to the HNRNPH2 PY-NLS to understand importin-NLS recognition and disruption in disease. HNRNPH2 RPGPY is a typical R-X-P-Y motif comprising PY-NLS epitopes 2 and 3, followed by an additional Karyopherin-β2-binding epitope, we term epitope 4, at residues DRP; no density is present for PY-NLS epitope 1. Disease variant mutations at epitopes 2-4 impair Karyopherin-β2 binding and cause aberrant cytoplasmic accumulation in cells, emphasizing the role of nuclear import defect in disease. Sequence/structure analysis suggests that strong PY-NLS epitopes 4 are rare and thus far limited to close paralogs of HNRNPH2, HNRNPH1, and HNRNPF. Epitope 4-binidng hotspot Karyopherin-β2 W373 corresponds to close paralog Karyopherin-β2b/Transportin-2 W370, a pathological variant site in neurodevelopmental abnormalities, suggesting that Karyopherin-β2b/Transportin-2-HNRNPH2/H1/F interactions may be compromised in the abnormalities.
External linksStructure / PubMed:37279758 / PubMed Central
MethodsEM (single particle)
Resolution3.17 Å
Structure data

40455

8sgh

EMDB-40455, PDB-8sgh:
Cryo-EM structure of Karyopherin-beta2 bound to HNRNPH2 PY-NLS
Method: EM (single particle) / Resolution: 3.17 Å

Source
  • homo sapiens (human)
KeywordsTRANSPORT PROTEIN / RNA-binding protein TNPO1 Cryo-EM KapB2 HNRNP

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