8SGH

Cryo-EM structure of Karyopherin-beta2 bound to HNRNPH2 PY-NLS

Summary for 8SGH

• Entry DOI: 10.2210/pdb8sgh/pdb
• EMDB information: 40455
• Descriptor: Transportin-1, Heterogeneous nuclear ribonucleoprotein H2, N-terminally processed (2 entities in total)
• Functional Keywords: rna-binding protein tnpo1 cryo-em kapb2 hnrnp, transport protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 115732.62

Authors

Gonzalez, A.,Fung, H.Y.J.,Chook, Y.M. (deposition date: 2023-04-12, release date: 2023-06-14, Last modification date: 2023-08-16)

Primary citation

Gonzalez, A.,Kim, H.J.,Freibaum, B.D.,Fung, H.Y.J.,Brautigam, C.A.,Taylor, J.P.,Chook, Y.M.
A new Karyopherin-beta 2 binding PY-NLS epitope of HNRNPH2 linked to neurodevelopmental disorders.
Structure, 31:924-934.e4, 2023

PubMed 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 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.

PubMed: 37279758
DOI: 10.1016/j.str.2023.05.010

Experimental method

ELECTRON MICROSCOPY (3.17 Å)