The 21.5-kDa isoform of myelin basic protein has a non-traditional PY-nuclear-localization signal

Smith, Graham; Seymour, Lauren V.; Boggs, Joan M.; Harauz, George

doi:10.1016/j.bbrc.2012.05.051

Cited by 18 publications

(17 citation statements)

References 46 publications

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“…The NLS for the 21.5‐kDa MBP isoform has recently been shown to reside within the highly conserved 26‐residue segment (VPWLKQSRSPLPSHARSRPGLCHMYK in the mouse) encoded by exon‐II, particularly via two putative non‐traditional PY‐NLS motifs identified by the pattern of ZX 2‐5 PB, where ‘Z’ is a basic residue, ‘X’ is any residue, and ‘B’ is a hydrophobic residue (Smith et al . ). Site‐directed mutagenesis of selected residues within this segment in red fluorescent protein (RFP)‐tagged constructs, prevented nuclear localization in N19‐OLGs, and highlighted the importance of the arginine and lysine residues within these motifs for trafficking this protein to the nucleus.…”

Section: The Exon‐ii‐containing Full‐length 215‐kda Isoform Is Transmentioning

confidence: 97%

Myelin management by the 18.5‐kDa and 21.5‐kDa classic myelin basic protein isoforms

Harauz

Boggs

2013

Journal of Neurochemistry

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The classic myelin basic protein (MBP) splice isoforms range in nominal molecular mass from 14 to 21.5 kDa, and arise from the gene in the oligodendrocyte lineage (Golli) in maturing oligodendrocytes. The 18.5-kDa isoform that predominates in adult myelin adheres the cytosolic surfaces of oligodendrocyte membranes together, and forms a two-dimensional molecular sieve restricting protein diffusion into compact myelin. However, this protein has additional roles including cytoskeletal assembly and membrane extension, binding to SH3-domains, participation in Fyn-mediated signaling pathways, sequestration of phosphoinositides, and maintenance of calcium homeostasis. Of the diverse post-translational modifications of this isoform, phosphorylation is the most dynamic, and modulates 18.5-kDa MBP's protein-membrane and proteinprotein interactions, indicative of a rich repertoire of functions.In developing and mature myelin, phosphorylation can result in microdomain or even nuclear targeting of the protein, supporting the conclusion that 18.5-kDa MBP has significant roles beyond membrane adhesion. The full-length, early-developmental 21.5-kDa splice isoform is predominantly karyophilic due to a non-traditional P-Y nuclear localization signal, with effects such as promotion of oligodendrocyte proliferation. We discuss in vitro and recent in vivo evidence for multifunctionality of these classic basic proteins of myelin, and argue for a systematic evaluation of the temporal and spatial distributions of these protein isoforms, and their modified variants, during oligodendrocyte differentiation. Keywords: cytoskeleton, Fyn-SH3, intrinsically disordered protein, myelin basic protein, oligodendrocyte, phosphorylation. J. Neurochem. (2013) 125, 334-361. What is myelin basic protein and what does it do?The 'classic' 18.5-kDa isoform of myelin basic protein (MBP) was first isolated more than 50 years ago as an encephalitogenic determinant (Roboz-Einstein et al. 1962;Carnegie and Lumsden 1966). This protein is an integral component of central nervous system (CNS) myelin, adhering the cytoplasmic leaflets of the oligodendrocyte (OLG) membrane to each other to form the major dense line observed in electron micrographs (Trapp and Kidd 2004). This fundamental role is demonstrated by the shiverer mutant mouse which has an ablation in the MBP gene, and whose CNS myelin is sparse and relatively unstructured (Dupouey Received December 19, 2012; revised manuscript received February 5, 2013; accepted February 5, 2013. Address correspondence and reprint requests to George Harauz, Department of Molecular and Cellular Biology, University of Guelph, 50 Stone Road East, Guelph, Ontario, N1G 2W1, Canada. E-mail: gharauz@uoguelph.ca Abbreviations used: CaM, calmodulin; CNS, central nervous system; Golli, gene in the oligodendrocyte lineage; IDP, intrinsically disordered protein; MAPK, mitogen-activated protein kinase; MAP, microtubuleassociated protein; MBP, myelin basic protein; MoRF, molecular recognition fragment; NLS, nuclear locali...

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Section: The Exon‐ii‐containing Full‐length 215‐kda Isoform Is Transmentioning

confidence: 97%

Myelin management by the 18.5‐kDa and 21.5‐kDa classic myelin basic protein isoforms

Harauz

Boggs

2013

Journal of Neurochemistry

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“…Here we have studied further the role of the 21.5‐kDa MBP isoform, which has an additional 26 amino acids encoded by exon II of the classic MBP gene that cause it to translocate to the nucleus (Smith et al, 2012c). Although both 18.5‐kDa and 21.5‐kDa isoforms are intrinsically disordered, one notable difference may be that the 21.5‐kDa isoform has greater potential to dimerize in vitro because of a single cysteinyl residue encoded by exon II (Nye et al, 1995); its in vivo quaternary structure is unknown.…”

Section: Discussionmentioning

confidence: 99%

“…The full‐length 21.5‐kDa transcript includes exon II (exon 6 in Golli numbering), and the 26‐residue exon II‐encoded segment is conserved in higher vertebrates (Smith et al, 2012c). One of the primary differences between the two classic MBP isoforms is that 21.5‐kDa MBP is targeted predominantly to the nucleus and 18.5‐kDa MBP to the cytoplasmic plasma membrane leaflet, within OLGs (Colman et al, 1990; Gillespie et al, 1990; Staugaitis et al, 1990; Allinquant et al, 1991; de Vries et al, 1997).…”

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confidence: 99%

“…At high N19‐OLG density in culture, the 21.5‐kDa isoform translocated from the nucleus to the cytoplasm (Smith et al, 2012b) and also after phorbol ester treatment of low‐confluence cultures (Smith et al, 2012a). We have recently shown that the 21.5‐kDa MBP isoform has a nontraditional PY‐nuclear localization signal (NLS) in the 26‐residue segment encoded by exon II (Smith et al, 2012c). Classic MBP isoforms are thus another example of proteins that play roles both at the plasma membrane and in the nucleus (Benmerah et al, 2003).…”

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Nucleus‐localized 21.5‐kDa myelin basic protein promotes oligodendrocyte proliferation and enhances neurite outgrowth in coculture, unlike the plasma membrane‐associated 18.5‐kDa isoform

Smith

Samborska

Hawley

et al. 2012

J of Neuroscience Research

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The classic myelin basic protein (MBP) family of central nervous system (CNS) myelin arises from transcription start site 3 of the Golli (gene of oligodendrocyte lineage) complex and comprises splice isoforms ranging in nominal molecular mass from 14 kDa to (full-length) 21.5 kDa. We have determined here a number of distinct functional differences between the major 18.5-kDa and minor 21.5-kDa isoforms of classic MBP with respect to oligodendrocyte (OLG) proliferation. We have found that, in contrast to 18.5-kDa MBP, 21.5-kDa MBP increases proliferation of early developmental immortalized N19-OLGs by elevating the levels of phosphorylated ERK1/2 and Akt1 kinases and of ribosomal protein S6. Coculture of N2a neuronal cells with N19-OLGs transfected with the 21.5-kDa isoform (or conditioned medium from), but not the 18.5-kDa isoform, caused the N2a cells to have increased neurite outgrowth and process branching complexity. These roles were dependent on subcellular localization of 21.5-kDa MBP to the nucleus and on the exon II-encoded segment, suggesting that the nuclear localization of early minor isoforms of MBP may play a crucial role in regulating and/or initiating myelin and neuronal development in the mammalian CNS. Keywords myelin basic protein; MBP; oligodendrocytes; myelination; live-cell imagingIn the central nervous system (CNS), myelin arises from oligodendrocytes (OLGs), a highly diverse and plastic lineage (Baumann and Pham-Dinh, 2001;Miller, 2002;Noble et al., 2004;Colognato and ffrench-Constant, 2004;Bradl and Lassmann, 2010 CIHR Author ManuscriptCIHR Author Manuscript CIHR Author Manuscript 2011). The OLGs proceed through a regulated differentiation pathway, culminating in myelination of axons (Pfeiffer et al., 1993;Miller, 1996). The OLG is at the mature stage when myelin basic protein (MBP) and proteolipid protein (PLP) are expressed, and extensive processes and myelin-like sheets form and extend around an axon. The MBP family comprises developmentally regulated members arising from different transcription start sites of the Golli (gene of oligodendrocyte lineage) complex, with further differential splicing and combinatorial posttranslational modifications Pribyl et al., 1993;Givogri et al., 2001). The "classic" MBP isoforms arise in more highly differentiated and mature OLGs, from transcription start site 3 of Golli, and comprise splice isoforms ranging in nominal molecular mass from 14 to 21.5 kDa. These MBPs are fundamental structural proteins of CNS myelin, particularly the predominant (in mature myelin) 18.5-kDa isoform, being essential for myelin development and stability (Readhead et al., 1990;Fitzner et al., 2006;Simons and Trotter, 2007; Aggarwal et al., 2011a,b;Simons et al., 2012).The 18.5-kDa MBP isoform is an intrinsically disordered protein with numerous conformational transitions and multiple binding partners, including cytoskeletal proteins, calcium-activated calmodulin, and SH3-domain-containing proteins, indicative of multifunctionality (for review see Harauz et al., 200...

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“…What is not clear yet is how the activation of maternal innate immune response led to an apparently sustained increase in the levels of this 21.5 KDa isoform. In contrast to other MBP isoforms, the 21.5 KDa MBP isoform has been shown to be localized in the nucleus of OPCs and promotes their proliferation 46,47. Such mitotic effect could be the mechanism underlying the observed increase in the cell density of OPCs in the corpus callosum of adult offspring born to dams given LPS during pregnancy.The impact of prenatal immune challenge on demyelination has been largely explored in an experimental model of demyelination, the experimental EAE 48.…”

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confidence: 94%

Impact of prenatal immune challenge on the demyelination injury during adulthood

et al. 2017

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The 21.5-kDa isoform of myelin basic protein has a non-traditional PY-nuclear-localization signal

Cited by 18 publications

References 46 publications

Myelin management by the 18.5‐kDa and 21.5‐kDa classic myelin basic protein isoforms

Myelin management by the 18.5‐kDa and 21.5‐kDa classic myelin basic protein isoforms

Nucleus‐localized 21.5‐kDa myelin basic protein promotes oligodendrocyte proliferation and enhances neurite outgrowth in coculture, unlike the plasma membrane‐associated 18.5‐kDa isoform

Impact of prenatal immune challenge on the demyelination injury during adulthood

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