Transportin-1: A Nuclear Import Receptor with Moonlighting Functions

Abstract

Transportin-1 (Trn1), also known as karyopherin-β2 (Kapβ2), is probably the best-characterized nuclear import receptor of the karyopherin-β family after Importin-β, but certain aspects of its functions in cells are still puzzling or are just recently emerging. Since the initial identification of Trn1 as the nuclear import receptor of hnRNP A1 ∼25 years ago, several molecular and structural studies have unveiled and refined our understanding of Trn1-mediated nuclear import. In particular, the understanding at a molecular level of the NLS recognition by Trn1 made a decisive step forward with the identification of a new class of NLSs called PY-NLSs, which constitute the best-characterized substrates of Trn1. Besides PY-NLSs, many Trn1 cargoes harbour NLSs that do not resemble the archetypical PY-NLS, which complicates the global understanding of cargo recognition by Trn1. Although PY-NLS recognition is well established and supported by several structures, the recognition of non-PY-NLSs by Trn1 is far less understood, but recent reports have started to shed light on the recognition of this type of NLSs. Aside from its principal and long-established activity as a nuclear import receptor, Trn1 was shown more recently to moonlight outside nuclear import. Trn1 has for instance been caught in participating in virus uncoating, ciliary transport and in modulating the phase separation properties of aggregation-prone proteins. Here, we focus on the structural and functional aspects of Trn1-mediated nuclear import, as well as on the moonlighting activities of Trn1.

Transportin 1 is a major nuclear import receptor of the nitric oxide synthase interacting protein

“…For TNPO1, the vast majority of cross-links was found within the first 200 amino acids of the protein. The interaction of TNPO1 with a classic M9-containing cargo, on the other hand, is known to involve rather the C-terminal portion of the import receptor ( 30 , 31 ). We therefore compared binding of full-length TNPO1 and N- and C-terminal deletion mutants to immobilized GST-M9 and GST-NOSIP.…”

“…The best-known interaction mode of TNPO1 with its cargoes is through a signal sequence termed PY-NLS (M9-sequence), first identified in hnRNPA1 ( 36 ) and later found in other proteins like hnRNP M, hnRNP D, FUS, TAP, and HCC1 ( 31 ). The PY-NLS, which consists of a hydrophobic or basic N-terminal motif followed by a conserved basic residue and a PY motif (R/H/K-X 2−5 -PY), binds to the C-terminal arch of TNPO1 ( 30 ).…”

Diverse roles of heterogeneous nuclear ribonucleoproteins in viral life cycle

“…Of note, hnRNP A1 was identified as the first cargo of Transportin-1 (Trn-1), which is a well-characterized nuclear import receptor (35,36). Trn-1 also imports other proteins of the hnRNP family such as hnRNP A/B, hnRNP D, hnRNP F, hnRNP H, hnRNP M (37). A schematic structural diagram of major hnRNPs, along with their size, major RNA binding domains, and localization signals are shown in Figure 1 and Table 1.…”

How Influenza Virus Uses Host Cell Pathways during Uncoating

“…In this way, larger molecules are selected by nuclear transport receptors (also called karyopherins) that carry their cargoes from one compartment to the other by crossing the nuclear envelope at the level of the nuclear pore complexes [ 239 , 240 ]. Importins mediate the nuclear import of cargos and transportin 1 (TNPO1, also known as importin-β2, KPNB2) is one of the best-characterized nuclear import receptors [ 241 ].…”