Myelin basic protein—diverse conformational states of an intrinsically unstructured protein and its roles in myelin assembly and multiple sclerosis

Harauz, George; Ishiyama, Noboru; Hill, Charles H.; Bates, Ian R.; Libich, David S.; Farès, Christophe

doi:10.1016/j.micron.2004.04.005

Cited by 226 publications

(210 citation statements)

References 483 publications

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“…Therefore, we expressed and purified a recombinant His-tagged human MBP protein, which lacked any post-translational modifications, and compared its activity with that of a purified human brain MBP. We expressed the 18.5-kDa isoform of MBP because this is the predominant species found in adult human brain (22,32). With regard to A␤ binding and inhibition of fibrillogenesis, the recombinant human MBP protein was comparable with MBP purified from human brain white matter.…”

Section: Discussionmentioning

confidence: 99%

“…This is also consistent with mouse brain MBP having activity comparable with that of human brain MBP. In adult mouse brain, the 14.3-kDa MBP predominates, whereas in adult human brain, the predominant form is the 18.5-kDa MBP (32)(33)(34)38). The major difference between these particular human and mouse MBP proteins resides in their C-terminal regions.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

N-terminal Domain of Myelin Basic Protein Inhibits Amyloid β-Protein Fibril Assembly

Liao

Hoos

Aucoin

et al. 2010

Journal of Biological Chemistry

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In the present study, we demonstrate that human MBP purified from either brain or a bacterial recombinant expression system comparably bound to A␤ and inhibited A␤ fibril assembly indicating that post-translational modifications are not required for this activity. We also show that purified mouse brain MBP and recombinantly expressed mouse MBP similarly inhibited A␤ fibril formation. Through a combination of biochemical and ultrastructural techniques, we demonstrate that the binding site for A␤ is located in the N-terminal 64 amino acids of MBP and that a stable peptide (MBP1) comprising these residues was sufficient to inhibit A␤ fibrillogenesis. Under conditions comparable with those used for A␤, the fibrillar assembly of amylin, another amyloidogenic peptide, was not inhibited by MBP1, although MBP1 still bound to it. This observation suggests that the potent inhibitory effect of MBP on fibril formation is not general to amyloidogenic peptides. Finally, MBP1 could prevent the cytotoxic effects of A␤ in primary cortical neurons. Our findings suggest that inhibition of A␤ fibril assembly by MBP, mediated through its N-terminal domain, could play a role in influencing amyloid formation in Alzheimer disease brain and corresponding mouse models. The histopathology of Alzheimer disease (AD)2 is characterized by the prominent presence of plaques of amyloid ␤-protein (A␤) in the brain parenchyma (1). Dystrophic neurons and neuronal loss are often associated with A␤ accumulation leading to the clinical manifestation of cognitive decline and memory loss. A␤ is derived from the amyloid ␤-protein precursor (A␤PP) through sequential proteolysis by ␤-and ␥-secretases yielding peptides of between 39 and 43 residues (2-5). These peptides exhibit a high propensity to self-assemble into ␤-sheet-containing oligomers and fibrils of which the oligomeric forms are widely believed to be the most toxic species of the peptide, responsible for the majority of neuronal loss (6). A condition known as cerebral amyloid angiopathy (CAA) is prevalently found in AD and is characterized by fibrillar deposition of A␤ along arteries and arterioles of the cerebral cortex, leptomeninges, and cerebral microvasculature (6 -8). Apart from the more typical CAA, which commonly occurs in AD, familial forms of CAA exist that are the result of specific point mutations within the A␤ sequence of the A␤PP gene (9 -15). Two well studied examples of familial CAA are Dutch type, resulting from an E22Q substitution in A␤ (9, 10), and Iowa type, resulting from a D23N substitution in A␤ (15).Elucidating the molecules and processes in brain that regulate A␤ assembly and accumulation as parenchymal plaques and cerebral vascular deposits is important for understanding the pathogenesis of AD and related disorders as well as for providing opportunities for development of potential therapeutic interventions. Previously, we found that myelin basic protein (MBP) strongly bound to a highly fibrillogenic A␤40 peptide that contains both the Dutch and Iowa mutations (A␤40DI)...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

N-terminal Domain of Myelin Basic Protein Inhibits Amyloid β-Protein Fibril Assembly

Liao

Hoos

Aucoin

et al. 2010

Journal of Biological Chemistry

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“…Due to its high charge and low overall hydrophobicity, there is significant intramolecular electrostatic repulsion in MBP; this results in MBP being an extended, intrinsically unstructured protein in solution [12,21].…”

Section: Introductionmentioning

confidence: 99%

Dynamic properties of a reconstituted myelin sheath

et al. 2010

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Abstract. Myelin is a multilamellar membrane which, wrapping the nerve axons, increases the efficiency of nervous signal transmission. Indeed, the molecular components of the myelin sheath interact tightly with each other and molecules on the axonal surface to drive myelination, to keep both myelin and the axon intact, and to transduce signals from myelin to the axon and vice versa. Myelin is strongly affected in human demyelinating diseases in both the central and peripheral nervous system (CNS and PNS, respectively). Despite the presence of a well-defined set of myelin-specific proteins, little is known about the structure and the dynamics of these proteins, their interactions with the membrane and their influence on myelin stability. We present here the first neutron scattering results on the dynamics of the myelin sheath in PNS and of the interaction between its constituents. Specifically, the human P2 protein is shown to stabilize the lipid membrane upon binding to it.

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“…It is known that the presence of intrinsic disorder can serve as one of the bottlenecks in structural characterization of a target protein that can affect several processes of the structure determination pipeline, such as expression and stability, 187,188 as well as solubility, 189,190 and predisposition for crystallization. 189,[191][192][193][194][195][196] In application to spondins and their partners, this hypothesis is supported by the observation that proteins with more predicted disorder typically have lower structure coverage. Data presented in our study revealed that spondins and their binding partners contain considerable levels of disorder and intrinsic disorder might be related to functionality of these proteins.…”

Section: Discussionmentioning

confidence: 93%

“…Similar to F-spondin, the FS of mindin is calcium-binding protein with Ca 2C being ligated by Asp 160 , Asp 188 , and Asp 192 . 106 The structure of the FS domain of mindin is characterized by the 8-stranded antiparallel b-sandwich topology containing 2 4-stranded b-sheets, b4b1b8b7 and b6b5b2b3 with 2 a-helices packed on one side of the b-sandwich.…”

Section: Mindin (Spondin-2 or Dil-1)mentioning

confidence: 99%

Intrinsic disorder in spondins and some of their interacting partners

Alowolodu

Johnson

Alashwal

et al. 2016

Intrinsically Disordered Proteins

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Spondins, which are proteins that inhibit and promote adherence of embryonic cells so as to aid axonal growth are part of the thrombospondin-1 family. Spondins function in several important biological processes, such as apoptosis, angiogenesis, etc. Spondins constitute a thrombospondin subfamily that includes F-spondin, a protein that interacts with Ab precursor protein and inhibits its proteolytic processing; R-spondin, a 4-membered group of proteins that regulates Wnt pathway and have other functions, such as regulation of kidney proliferation, induction of epithelial proliferation, the tumor suppressant action; M-spondin that mediates mechanical linkage between the muscles and apodemes; and the SCO-spondin, a protein important for neuronal development. In this study, we investigated intrinsic disorder status of human spondins and their interacting partners, such as members of the LRP family, LGR family, Frizzled family, and several other binding partners in order to establish the existence and importance of disordered regions in spondins and their interacting partners by conducting a detailed analysis of their sequences, finding disordered regions, and establishing a correlation between their structure and biological functions.

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Myelin basic protein—diverse conformational states of an intrinsically unstructured protein and its roles in myelin assembly and multiple sclerosis

Cited by 226 publications

References 483 publications

N-terminal Domain of Myelin Basic Protein Inhibits Amyloid β-Protein Fibril Assembly

N-terminal Domain of Myelin Basic Protein Inhibits Amyloid β-Protein Fibril Assembly

Dynamic properties of a reconstituted myelin sheath

Intrinsic disorder in spondins and some of their interacting partners

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