9nz1 | pdb_00009nz1
Adeno-associated virus serotype 11 basic regions in complex with importin alpha 2
Structural highlights
FunctionIMA1_MOUSE Functions in nuclear protein import as an adapter protein for nuclear receptor KPNB1. Binds specifically and directly to substrates containing either a simple or bipartite NLS motif. Docking of the importin/substrate complex to the nuclear pore complex (NPC) is mediated by KPNB1 through binding to nucleoporin FxFG repeats and the complex is subsequently translocated through the pore by an energy requiring, Ran-dependent mechanism. At the nucleoplasmic side of the NPC, Ran binds to importin-beta and the three components separate and importin-alpha and -beta are re-exported from the nucleus to the cytoplasm where GTP hydrolysis releases Ran from importin. The directionality of nuclear import is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus. Publication Abstract from PubMedAdeno-associated viruses (AAVs) are widely acknowledged as versatile vectors for gene therapy due to their non-pathogenic nature, inherent capacity for tissue-specific targeting, and their potential for customizable engineering. The N terminus of the AAV capsid protein VP1 plays a pivotal role in guiding AAV capsids into the cell nucleus. However, the precise dynamics of the interaction between the VP1 protein and host nuclear transport proteins, especially across diverse AAV serotypes, remain incompletely understood. AAV11 has emerged as a promising alternative for individuals with elevated antibody titers against AAV2, and in the field of neuroscience, it has demonstrated a strong capability for mapping and manipulating neural circuits, offering the potential for treating neurological and neurodegenerative disorders. In this study, we characterize the molecular interface between AAV11 VP1 and host importin-alpha (IMPalpha). Structural and biochemical analyses reveal that the basic regions BR1 and BR3 of the VP1 N-terminal domain engage IMPalpha in a bipartite nuclear localization signal (NLS)-like manner. These findings provide mechanistic insight into VP1-IMPalpha recognition and suggest a role for these interactions in AAV11 nuclear import. While direct functional evidence is pending, this work establishes the molecular basis for VP1-host protein binding and informs future capsid engineering. Elucidation of the binding interaction interface between AAV serotype 11 capsid protein and host nuclear import proteins.,Hoad M, Nematollahzadeh S, Roby JA, Alvisi G, Forwood JK Mol Ther Methods Clin Dev. 2025 Nov 10;33(4):101630. doi: , 10.1016/j.omtm.2025.101630. eCollection 2025 Dec 11. PMID:41376776[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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