A new Karyopherin-β2 binding PY-NLS epitope of HNRNPH2 linked to neurodevelopmental disorders

Abner Gonzalez, Hong Joo Kim, Brian D. Freibaum, Ho Yee Joyce Fung, Chad A. Brautigam, J. Paul Taylor, Yuh Min Chook

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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 206RPGPY210 is a typical R-X2-4-P-Y motif comprising PY-NLS epitopes 2 and 3, followed by an additional Karyopherin-β2-binding epitope, we term epitope 4, at residues 211DRP213; 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.

Original languageEnglish (US)
Pages (from-to)924-934.e4
JournalStructure
Volume31
Issue number8
DOIs
StatePublished - Aug 3 2023

Keywords

  • HNRNPH1
  • HNRNPH2
  • Karyopherin
  • Neurodevelopmental disorder
  • Nuclear Import
  • PY-NLS
  • Transportin-1
  • Transportin-2
  • hnRNP
  • importin

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

Fingerprint

Dive into the research topics of 'A new Karyopherin-β2 binding PY-NLS epitope of HNRNPH2 linked to neurodevelopmental disorders'. Together they form a unique fingerprint.

Cite this