Recognition motifs for importin 4 [(L)PPRS(G/P)P] and importin 5 [KP(K/Y)LV] binding, identified by bio-informatic simulation and experimental in vitro validation

Panagiotopoulos, Athanasios A.; Kalyvianaki, Konstantina; Tsodoulou, Paraskevi K.; Darivianaki, Maria N.; Dellis, Dimitris; Notas, George; Daskalakis, Vangelis; Theodoropoulos, Panayiotis A.; Panagiotidis, Christos Α.; Castanas, Elias; Kampa, Marilena

doi:10.1016/j.csbj.2022.10.015

Cited by 3 publications

(1 citation statement)

References 98 publications

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“…Many proteins which localize and function in the nucleus contain neither a classical nor a PY-type NLS, raising the question how and by which importin(s) these proteins are recognized and guided through the NPC. In silico approaches have identified novel consensus NLSs for IPO4, IPO5 [ 75 ] and IPO7 [ 76 ] with the help of molecular docking simulations based on interactions with known and suspected cargo (IPO4: LPPRS(G/P)P; IPO5: KP(K/Y)LV; IPO7: EKRKI(E/R)(K/L/R/S/T). These putative NLSs were validated in cells by measuring the subcellular localization of GFP-NLS fusion constructs upon siRNA-mediated knock-down of the corresponding NIR [ 75 , 76 ].…”

Section: Nuclear-transport Proteins Associate With Cargo Proteins And...mentioning

confidence: 99%

Nuclear-import receptors as gatekeepers of pathological phase transitions in ALS/FTD

Khalil,

Linsenmeier,

Smith

et al. 2024

Mol Neurodegeneration

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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders on a disease spectrum that are characterized by the cytoplasmic mislocalization and aberrant phase transitions of prion-like RNA-binding proteins (RBPs). The common accumulation of TAR DNA-binding protein-43 (TDP-43), fused in sarcoma (FUS), and other nuclear RBPs in detergent-insoluble aggregates in the cytoplasm of degenerating neurons in ALS/FTD is connected to nuclear pore dysfunction and other defects in the nucleocytoplasmic transport machinery. Recent advances suggest that beyond their canonical role in the nuclear import of protein cargoes, nuclear-import receptors (NIRs) can prevent and reverse aberrant phase transitions of TDP-43, FUS, and related prion-like RBPs and restore their nuclear localization and function. Here, we showcase the NIR family and how they recognize cargo, drive nuclear import, and chaperone prion-like RBPs linked to ALS/FTD. We also discuss the promise of enhancing NIR levels and developing potentiated NIR variants as therapeutic strategies for ALS/FTD and related neurodegenerative proteinopathies. Graphical Abstract

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Section: Nuclear-transport Proteins Associate With Cargo Proteins And...mentioning

confidence: 99%

Nuclear-import receptors as gatekeepers of pathological phase transitions in ALS/FTD

Khalil,

Linsenmeier,

Smith

et al. 2024

Mol Neurodegeneration

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Nuclear translocation of the membrane oxoeicosanoid/androgen receptor, OXER1: Possible mechanisms involved

Malamos,

Kalyvianaki,

Panagiotopoulos

et al. 2024

Molecular and Cellular Endocrinology

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Importins involved in the nuclear transportation of steroid hormone receptors: In silico and in vitro data

et al. 2022

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The nuclear receptor superfamily (NRS) consists of 48 receptors for lipophilic substances and is divided into 7 different subfamilies, with subfamily 3 comprising steroid hormone receptors. Several nuclear receptors usually bind their cognate ligands in the cytosol and the complex (mono- or dimerized) is transported to the nucleus, where it acts as a transcription initiating factor for a number of genes. The general structure of nuclear receptors consists of an N-terminal activating domain (A/B), important for the binding of activating or inhibitory co-factors, the DNA-binding domain (C), responsible for the association of the receptor-ligand-co-factor complex to the nucleus, the ligand-AF2 domain (E/F), where ligand binding occurs as well as that of ligand-dependent activating/inhibiting factors, and a flexible/non-structured domain (D), linking the DBD and LBD, called hinge region, on which a significant number of post-translational modifications occur. This hinge domain, for the sub-class of steroid receptors, is a non-structured domain and was reported as mainly responsible for the nuclear transport of steroid receptors, since it contains a specific amino acid sequence (Nuclear Localization Signal-NLS), recognized by importin α. In addition to the importin α/β complex, a number of other importins have been discovered and reported to be responsible for the nuclear transport of a number of significant proteins; however, the corresponding recognition sequences for these importins have not been identified. Recently, we have reported the identification of the NLS sequences for importins 4, 5 and 7. In this work, we provide in silico data, followed by experimental in vitro validation, showing that these alternative importins are responsible for the nuclear transportation of steroid hormone receptors such as ERα, AR and PR, and therefore they may consist of alternative targets for the pharmacological manipulation of steroid hormone actions. Moreover, we provide additional in silico data for the hinge region of steroid hormone receptors which is highly enriched with NLS sequences for importins 4, 5 and 7, in addition to the recognition NLS for importin α/β.

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Recognition motifs for importin 4 [(L)PPRS(G/P)P] and importin 5 [KP(K/Y)LV] binding, identified by bio-informatic simulation and experimental in vitro validation

Cited by 3 publications

References 98 publications

Nuclear-import receptors as gatekeepers of pathological phase transitions in ALS/FTD

Nuclear-import receptors as gatekeepers of pathological phase transitions in ALS/FTD

Nuclear translocation of the membrane oxoeicosanoid/androgen receptor, OXER1: Possible mechanisms involved

Importins involved in the nuclear transportation of steroid hormone receptors: In silico and in vitro data

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