The proline-rich region of 18.5 kDa myelin basic protein binds to the SH3-domain of Fyn tyrosine kinase with the aid of an upstream segment to form a dynamic complex<i>in vitro</i>

Avila, Miguel De; Vassall, Kenrick A.; Smith, Graham; Bamm, Vladimir V.; Harauz, George

doi:10.1042/bsr20140149

Cited by 16 publications

(24 citation statements)

References 87 publications

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“…MBP takes part in several protein-protein interactions, and thus acts as an effector. MBP interacts with Fyn kinase [78][79][80], cytoskeletal elements [78,81], and calmodulin, the latter interaction being dependent on Ca 2+ [21,[82][83][84]. The interaction with Fyn kinase is mediated via the SH3 domain, which MBP binds through a conserved PXXP motif.…”

Section: Myelin Basic Proteinmentioning

confidence: 99%

“…The interaction with Fyn kinase is mediated via the SH3 domain, which MBP binds through a conserved PXXP motif. The interaction has a potential impact on oligodendrocytic differentiation, as Fyn signaling is important during myelin development [79,80]. Oligodendrocyte process growth is thought to be modulated by the interaction of MBP with the cytoskeleton [78,81], which in turn is affected by the interaction between MBP and calmodulin [21,85].…”

Section: Myelin Basic Proteinmentioning

confidence: 99%

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Flexible Players within the Sheaths: The Intrinsically Disordered Proteins of Myelin in Health and Disease

Raasakka

Kursula

2020

Cells

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Myelin ensheathes selected axonal segments within the nervous system, resulting primarily in nerve impulse acceleration, as well as mechanical and trophic support for neurons. In the central and peripheral nervous systems, various proteins that contribute to the formation and stability of myelin are present, which also harbor pathophysiological roles in myelin disease. Many myelin proteins have common attributes, including small size, hydrophobic segments, multifunctionality, longevity, and regions of intrinsic disorder. With recent advances in protein biophysical characterization and bioinformatics, it has become evident that intrinsically disordered proteins (IDPs) are abundant in myelin, and their flexible nature enables multifunctionality. Here, we review known myelin IDPs, their conservation, molecular characteristics and functions, and their disease relevance, along with open questions and speculations. We place emphasis on classifying the molecular details of IDPs in myelin, and we correlate these with their various functions, including susceptibility to post-translational modifications, function in protein–protein and protein–membrane interactions, as well as their role as extended entropic chains. We discuss how myelin pathology can relate to IDPs and which molecular factors are potentially involved.

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Section: Myelin Basic Proteinmentioning

confidence: 99%

Section: Myelin Basic Proteinmentioning

confidence: 99%

Flexible Players within the Sheaths: The Intrinsically Disordered Proteins of Myelin in Health and Disease

Raasakka

Kursula

2020

Cells

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show abstract

Section: Myelin Basic Proteinmentioning

confidence: 99%

“…The interaction with Fyn kinase is mediated via the SH3 domain, which MBP binds through a conserved PXXP motif. The interaction has a potential impact on oligodendrocytic differentiation, as Fyn signalling is important during myelin development [79,80]. Oligodendrocyte process growth is thought to be modulated by the interactions of MBP with the cytoskeleton [78,81], which in turn is affected by the interaction between MBP and calmodulin [21,85].…”

Section: Myelin Basic Proteinmentioning

confidence: 99%

Flexible Players within the Sheaths: The Intrinsically Disordered Proteins of Myelin in Health and Disease

Raasakka

Kursula

2020

Preprint

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Myelin ensheathes selected axonal segments within the nervous system, resulting primarily in nerve impulse acceleration, as well as mechanical and trophic support for neurons. In the central and peripheral nervous systems, various proteins that contribute to the formation and stability of myelin are present, which also harbour pathophysiological roles in myelin disease. Many myelin proteins share common attributes, including small size, high hydrophobicity, multifunctionality, longevity, and intrinsic disorder. With recent advances in protein biophysical characterization and bioinformatics, it has become evident that intrinsically disordered proteins (IDPs) are abundant in myelin, and their flexible nature enables multifunctionality. Here, we review known myelin IDPs, their conservation, molecular characteristics and functions, and their disease relevance, along with open questions and speculations. We place emphasis on classifying the molecular details of IDPs in myelin and correlate these with their various functions, including susceptibility to post-translational modifications, function in protein-protein and protein-membrane interactions, as well as their role as extended entropic chains. We discuss how myelin pathology can relate to IDPs and which molecular factors are potentially involved.

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“…Recent work has demonstrated that U24-6A can be phosphorylated by MAPK, albeit less effectively than MBP13. It has also been shown that U24-6A can associate with Fyn SH3, but again does so more weakly than MBP ( K D = 5 mM for U24-6A14 versus 4-8 μM for MBP15). These findings suggested that although U24-6A may mimic MBP, it most likely does not interfere directly with MBP function.…”

mentioning

confidence: 99%

U24 from Roseolovirus interacts strongly with Nedd4 WW Domains

Sang

Zhang

Scott

et al. 2017

Sci Rep

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U24 is a protein found in both roseoloviruses Human Herpes Virus type 6 and 7 (HHV-6 and HHV-7), with an N-terminus that is rich in prolines (PY motif in both HHV-6A and 7; PxxP motif in HHV-6A). Previous work has shown that the interaction between U24 and WW domains is important for endocytic recycling of T-cell receptors, but a cognate ligand was never identified. In this contribution, data was obtained from pull-downs, ITC, NMR and molecular dynamics simulations to show that a specific interaction exists between U24 and Nedd4 WW domains. ITC experiments were also carried out for U24 from HHV-6A phosphorylated at Thr6 (pU24-6A) and a peptide containing the PY motif from Nogo-A, a protein implicated in both the initial inflammatory and the neurodegenerative phases of multiple sclerosis (MS). The results suggest that phosphorylation of U24 from HHV-6A may be crucial for its potential role in MS.Roseoloviruses, which include human herpes virus type 6A (HHV-6A), HHV-6B and HHV-7, are ubiquitous and highly prevalent. They have been found to be implicated in several neurological diseases, including encephalitis, epilepsy, and multiple sclerosis (MS) [1][2][3][4] . MS is a neurological inflammatory disease in the central nervous system (CNS). The exact cause of MS is unknown, but it has been suggested that one or more viruses may be possible triggers 2,5,6 . U24 is a putative tail-anchored membrane protein that is unique to roseoloviruses 7 . It is expressed in infected cells during the early stages of viral infection 8 . Although the exact function of U24 has not been identified, a number of studies have demonstrated a potential link between U24 and MS 9,10 .One possible way in which U24 may be implicated in MS is through the mimicry of myelin basic protein (MBP) because the two proteins share a seven amino acid stretch that contains a PxxP motif (Fig. 1a). This segment is essential for MBP to participate in Fyn-mediated signalling pathways by a direct but non-canonical association with the Fyn-SH3 domain 11 . Disruption of these signalling pathways has a large impact on oligodendrocyte differentiation and maturation, processes that are perturbed in MS patients. Within this PxxP motif and just before it are two threonine residues (T95 and T98), which can be phosphorylated. Phosphorylation has been shown to affect the local structure of MBP and its disposition on the membrane surface 12 . U24-6A shares with MBP both the PxxP motif and a threonine at an analogous position to T98 (Fig. 1a). Recent work has demonstrated that U24-6A can be phosphorylated by MAPK, albeit less effectively than MBP 13 . It has also been shown that U24-6A can associate with Fyn SH3, but again does so more weakly than MBP (K D = 5 mM for U24-6A 14 versus 4-8 μ M for MBP 15 ). These findings suggested that although U24-6A may mimic MBP, it most likely does not interfere directly with MBP function.Within the proline rich region of U24 is a PY motif that is conserved in both HHV-6A and HHV-7 (Fig. 1a). This motif was found to be responsible for ...

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The proline-rich region of 18.5 kDa myelin basic protein binds to the SH3-domain of Fyn tyrosine kinase with the aid of an upstream segment to form a dynamic complexin vitro

Cited by 16 publications

References 87 publications

Flexible Players within the Sheaths: The Intrinsically Disordered Proteins of Myelin in Health and Disease

Flexible Players within the Sheaths: The Intrinsically Disordered Proteins of Myelin in Health and Disease

Flexible Players within the Sheaths: The Intrinsically Disordered Proteins of Myelin in Health and Disease

U24 from Roseolovirus interacts strongly with Nedd4 WW Domains

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