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Nesprins: from the Nuclear Envelope and Beyond

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Nesprins: from the Nuclear Envelope and Beyond expert reviews http://www.expertreviews.org/ in molecular medicine Nesprins: from the nuclear envelope and beyond Dipen Rajgor and Catherine M. Shanahan* Nuclear envelope spectrin-repeat proteins (Nesprins), are a novel family of nuclear and cytoskeletal proteins with rapidly expanding roles as intracellular scaffolds and linkers. Originally described as proteins that localise to the nuclear envelope (NE) and establish nuclear-cytoskeletal connections, nesprins have now been found to comprise a diverse spectrum of tissue specific isoforms that localise to multiple sub-cellular compartments. Here, we describe how nesprins are necessary in maintaining cellular architecture by acting as essential scaffolds and linkers at both the NE and other sub-cellular domains. More importantly, we speculate how nesprin mutations may disrupt tissue specific nesprin scaffolds and explain the tissue specific nature of many nesprin-associated diseases, including laminopathies. The eukaryotic cytoplasm contains three major composed of three α-helical bundles with a left- types of cytoskeletal filaments: Filamentous- handed twist, and its primary function is to actin (F-actin), microtubules (MTs) and provide docking sites for proteins and other intermediate filaments (IFs). These components higher order complexes (Refs 3, 4). Although are organised in a manner that provides the cell most SR proteins contain CHDs, some possess with an internal framework fundamental for motifs which can interact with other cytoskeletal many processes, such as controlling cellular components, allowing linkage of SR-associated shape, polarity, adhesion and migration, complexes to filamentous structures other than cytokinesis, inter- and intracellular F-actin. In addition, these motifs allow cross- Nesprins: from the nuclear envelope and beyond communication and trafficking of organelles, linking between different filaments and dynamic vesicles, proteins and RNA (Refs 1, 2). re-modelling of the cells internal framework in For cells to utilise the cytoskeleton in these response to altered mechanical needs (Refs 5, 6, processes, scaffold or linker proteins are 7). The SR family is composed of a growing list required to attach cytosolic components to these of proteins that include α-actinins, α/β- dynamic filaments. The spectrin-repeat (SR) spectrins, dystrophins and spectraplakins. family of proteins are a prime example of such Family members are distinguished by unique linkers. The majority of family members are structural domains, which give the individual typically characterised by a pair of N-terminal family members their specialised functions. For calponin homology domains (CHDs) that bind example, the C-terminal Pleckstrin Homology F-actin, followed by a rod-like structure domain of β-spectrins facilitate membrane composed of multiple SRs. A single SR is attachment to the cell surface and organelles, the James Black Centre, Cardiovascular Division, King’s College London, 125 Coldharbour lane, London SE5 9NU, UK *Corresponding author: C.M. Shanahan, James Black Centre, Cardiovascular Division, King’s College London, 125 Coldharbour lane, London SE5 9NU, UK. E-mail: [email protected] 1 Accession information: doi:10.1017/erm.2013.6; Vol. 15; e5; July 2013 © Cambridge University Press 2013. Re-use permitted under a Creative Commons Licence – by-nc-sa. Downloaded from https://www.cambridge.org/core. IP address: 170.106.35.93, on 02 Oct 2021 at 04:50:29, subject to the Cambridge Core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/10.1017/erm.2013.6 expert reviews http://www.expertreviews.org/ in molecular medicine WW and Zn-fingers of dystrophins associate with of tissue specific nesprin-1 and nesprin-2 the dystroglycan complex spanning the plasma isoforms generated through alternative membrane to provide extracellular matrix transcription (Ref. 18). Many of these isoforms attachment and the GAR domains of exclude the C-terminal KASH domain and spectraplakins associate with MTs and act as localise to various sub-cellular compartments, cytoskeletal cross-linkers (Refs 8, 9, 10, 11, 12, 13). supporting additional functions for nesprins Nuclear envelope spectrin-repeat proteins other than NE linkage. (Nesprins), are the latest members of the SR This review focuses on summarising recent super family to be identified. They contain a findings in which scaffolding roles for nesprins unique evolutionary conserved C-terminal have been identified at the NE, and beyond. Klarsicht, ANC-1 and Syne Homology (KASH) Furthermore, we speculate that many of the transmembrane domain that specifically recruits tissue specific diseases resulting from nesprin the nesprins to the nuclear envelope (NE). To mutations, including cardiac and skeletal muscle date, four separate nesprin genes have been dysfunctions in Emery Dreifuss Muscular identified in vertebrates, which encode proteins Dystrophy (EDMD), cerebellar defects in with distinct cellular functions. Nesprin-1 and autosomal recessive cerebellar ataxia 1 (ARCA1), nesprin-2 are the largest SR proteins with tendon contractures in autosomal recessive molecular weights of ~1000 and ~800 kDa, arthrogryposis multiplex congenita (AMC), respectively, and connect the NE to F-actin cardiac defects in dilated cardiomyopathy through their pair of N-terminal CHDs. (DCM) and major depression in bipolar disease, Nesprin-3 and nesprin-4, with molecular maybe a consequence of defects in the weights of ~110 and ~42 kDa, respectively, lack production or scaffolding functions of a N-terminal CHDs (Refs 14, 15, 16, 17). Instead, subset of tissue specific nesprin isoforms, and nesprin-3 contains a plectin-binding domain thus, in some instances, be completely which links the NE to the cytoplasmic IF independent of NE-cytoskeletal linkage (Refs 19, networks. Nesprin-4 associates with kif5b, a 20, 21, 22, 23). subunit of the MT motor protein kinesin-1, downstream of its single SR (Refs 16, 17) Nesprins link the NE to the cytoskeleton (Fig. 1). The ability of the nesprins to localise to and nuclear lamina the NE and interact with cytoskeletal proteins, The nucleus is surrounded by a system of two initially led to the assumption that their primary concentric membranes, called the inner nuclear purpose was to act as cytoskeletal-NE linkers. membrane (INM) and the outer nuclear Excitingly, recent developments in nesprin membrane (ONM). Together, these two biology have identified an expansive collection membranes make up the NE and separate the Nesprins: from the nuclear envelope and beyond Nesprin-1 Nesprin-2 Calponin Homology domain Nesprin-3 Spectrin repeat KASH domain Nesprin-4 Figure 1. The nesprin family. The nesprin family is composed of four members, all of which contain a C- terminal nuclear envelope (NE) targeting Klarsicht, ANC-1 and Syne Homology (KASH) domain, and one or more spectrin-repeats (SRs). Nesprin-1 contains 74 SRs and binds to F-actin through its N-terminal calponin homology domains (CHDs). The shorter nesprin-2 protein is composed of 56 SRs, and like nesprin-1 is able to bind F-actin through its N-terminal CHDs. Nesprin-3 contains 8 SRs and interacts with the versatile cytoskeletal cross-linker plectin in a manner that allows nesprin-3 to associate with intermediate filaments (IFs). Nesprin-4 possesses only a single SR and interacts with kif5b, a subunit of the microtubule (MT) motor kinesin-1. 2 Accession information: doi:10.1017/erm.2013.6; Vol. 15; e5; July 2013 © Cambridge University Press 2013. Re-use permitted under a Creative Commons Licence – by-nc-sa. Downloaded from https://www.cambridge.org/core. IP address: 170.106.35.93, on 02 Oct 2021 at 04:50:29, subject to the Cambridge Core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/10.1017/erm.2013.6 expert reviews http://www.expertreviews.org/ in molecular medicine cells nuclear contents from the cytosol. Although stoichiometry ratio (Ref. 29). Although these the ONM and INM are a single continuous joint oligomeric structures are yet to be proved membrane, perforated by nuclear pore in vivo, hypothetically any one of the many ONM complexes and separated by a lumen, nesprin variants (see below) could associate in macromolecular compositions of the two sides any combination with a trimer of SUN domain vary. The ONM has a similar composition to proteins, allowing a large and mixed plethora of that of the adjoined endoplasmic reticulum, LINCs to form. with the addition of full-length nesprins-1, -2, -3 Nesprin-1α, which is enriched in cardiac, and -4 that link the NE to components of the skeletal and smooth muscle, forms anti-parallel cytoskeleton (Refs 15, 16, 17). The INM hosts a homodimers within the INM (Ref. 36). The unique collection of transmembrane proteins, significance of this dimerisation event remains which link the INM to the underlying nuclear unclear, but may provide additional mechanical lamina and chromatin (Refs 24, 25, 26, 27, 28). strength to nuclei that are constantly exposed to At the NE, the C-terminal sequence of nesprin contractile strain, by forming complex KASH domains bind to the C-terminal end of connections with the underlying nuclear lamina the trimeric INM SUN (Sad1p-UNC-84) domain and other interacting partners. proteins, SUN1 and SUN2, within the NE lumen In addition, nesprin-1 and nesprin-2 giants (i.e. (Refs 29, 30). The N-terminal tail of the trimeric full-length nesprin-1 and nesprin-2 isoforms) SUN proteins interacts with the nuclear lamina dimerise with nesprin-3 at the ONM to form a underlying the nuclear interior (Refs 29, 31, 32). meshwork composed of peri-nuclear The nuclear lamina, composed of type-V IF cytoskeletal filaments around the nuclear lamin proteins, forms a mechanical fibrous cage periphery, which becomes disorganised when around the interior surface of the NE which nesprin LINCS are disrupted (Refs 40, 41, 42). provides structural support to the nucleus and This meshwork may supply the necessary scaffolds nuclear signalling proteins, framework and act as a cushion for LINC transcription factors and chromatin (Refs 24, 27, complex functions that put considerable strain 28).
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