Phosphorylation of U24 from Human Herpes Virus type 6 (HHV‐6) and its potential role in mimicking myelin basic protein (MBP) in multiple sclerosis

Tait, Andrew R.; Straus, Suzana K.

doi:10.1016/j.febslet.2008.06.050

Cited by 23 publications

(28 citation statements)

References 32 publications

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“…ICP27 is involved in a series of processes in the nucleus and the cytoplasm, where it is attributed to a number of different protein interactions. Host protein-protein interactions are often regulated by phosphorylation, and phosphorylation events are reported to regulate a number of herpesvirus proteins (39)(40)(41)(42)(43). ICP27 is observed to have both stable and transient phosphorylations (44).…”

Section: Resultsmentioning

confidence: 99%

Structure of the C-Terminal Domain of the Multifunctional ICP27 Protein from Herpes Simplex Virus 1

Patel

Dahlroth

Rajakannan

et al. 2015

J Virol

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Herpesviruses are nuclear-replicating viruses that have successfully evolved to evade the immune system of humans, establishing lifelong infections. ICP27 from herpes simplex virus is a multifunctional regulatory protein that is functionally conserved in all known human herpesviruses. It has the potential to interact with an array of cellular proteins, as well as intronless viral RNAs. ICP27 plays an essential role in viral transcription, nuclear export of intronless RNAs, translation of viral transcripts, and virion host shutoff function. It has also been implicated in several signaling pathways and the prevention of apoptosis. Although much is known about its central role in viral replication and infection, very little is known about the structure and mechanistic properties of ICP27 and its homologs. We present the first crystal structure of ICP27 C-terminal domain at a resolution of 2.0 Å. The structure reveals the C-terminal half of ICP27 to have a novel fold consisting of ␣-helices and long loops, along with a unique CHCC-type of zinc-binding motif. The two termini of this domain extend from the central core and hint to possibilities of making interactions. ICP27 essential domain is capable of forming self-dimers as seen in the structure, which is confirmed by analytical ultracentrifugation study. Preliminary in vitro phosphorylation assays reveal that this domain may be regulated by cellular kinases. IMPORTANCE ICP27 is a key regulatory protein of the herpes simplex virus and has functional homologs in all known human herpesviruses.Understanding the structure of this protein is a step ahead in deciphering the mechanism by which the virus thrives. In this study, we present the first structure of the C-terminal domain of ICP27 and describe its novel features. We critically analyze the structure and compare our results to the information available form earlier studies. This structure can act as a guide in future experimental designs and can add to a better understanding of mechanism of ICP27, as well as that of its homologs. Herpes simplex virus (HSV) and other human herpesviruses (HHVs; e.g., Epstein-Barr virus and varicella-zoster virus) have evolved a unique strategy of virion host shutoff, in which they efficiently suppress the host protein synthesis. At the onset of the lytic phase, viral immediate-early (IE) genes are expressed first. These IE proteins are responsible for inducing the expression of viral early and late genes. The key IE protein of HSV, infectious cell protein 27 (ICP27), helps in the host shutoff function (1, 2). This 63-kDa protein consists of 512 amino acids and is involved in multiple functions, such as stalling host pre-RNA processing, exporting intronless viral mRNAs out of the nucleus, shuttling between host nucleus and cytoplasm facilitated by its nuclear export signal (NES) and nuclear localization signal (NLS), and interacting with RNA via its RGG box (3, 4). Most of these functions are conserved across the Herpesviridae family, and ICP27 homologs are present in all kno...

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Section: Resultsmentioning

confidence: 99%

Structure of the C-Terminal Domain of the Multifunctional ICP27 Protein from Herpes Simplex Virus 1

Patel

Dahlroth

Rajakannan

et al. 2015

J Virol

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“…This was associated with febrile illness, delayed transplant engraftment, and neurological involvement, up to lethal encephalitis (5,13,34,46). HHV-6A has thus far no clear disease association, although several studies have suggested central nervous system (CNS) tropism, including aggravation of symptoms in patients with multiple sclerosis (MS) (6,14,33,41).…”

mentioning

confidence: 99%

The DR1 and DR6 First Exons of Human Herpesvirus 6A Are Not Required for Virus Replication in Culture and Are Deleted in Virus Stocks That Replicate Well in T-Cell Lines

Borenstein

Zeigerman

Frenkel

2010

J Virol

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“…The extent of phosphorylation of U24, however, is much weaker than that of MBP. 6 Here we find that a binding interaction between U24 and Fyn-SH3 exists, but it is again most likely much weaker than the interaction between MBP and Fyn-SH3. Although a K D value was never reported for MBP/Fyn-SH3, a crude estimate based on the data reported in ref 15 can be made (K D ≈ 0.1−1 mM).…”

Section: ■ Discussionmentioning

confidence: 93%

“…6,20 The mass of the isolated mutant NΔ9-U24 protein was obtained by matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry, which confirmed that the protein had the desired mutation, having an N-terminal sequence of nine amino acids Figure 1. Sequences of MBP (residues 89−103, numbering used to correspond to numbering in the murine classic 18.5 kDa MBP isoform 17 ), U24 from HHV-6A (residues 1−15), and U24 from HHV-7 (residues 1−15).…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

Probing the Interaction between U24 and the SH3 Domain of Fyn Tyrosine Kinase

et al. 2014

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The putative membrane protein U24 from HHV-6A shares a seven-residue sequence identity (which includes a PxxP motif) with myelin basic protein (MBP), a protein responsible for the compaction of the myelin sheath in the central nervous system. U24 from HHV-6A also shares a PPxY motif with U24 from the related virus HHV-7, allowing them both to block early endosomal recycling. Recently, MBP has been shown to have protein-protein interactions with a range of proteins, including proteins containing SH3 domains. Given that this interaction is mediated by the proline-rich segment in MBP, and that similar proline-rich segments are found in U24, we investigate here whether U24 also interacts with SH3 domain-containing proteins and what the nature of that interaction might be. The implications of a U24-Fyn tyrosine kinase SH3 domain interaction are discussed in terms of the hypothesis that U24 may function like MBP through molecular mimicry, potentially contributing to the disease state of multiple sclerosis or other demyelinating disorders.

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Phosphorylation of U24 from Human Herpes Virus type 6 (HHV‐6) and its potential role in mimicking myelin basic protein (MBP) in multiple sclerosis

Cited by 23 publications

References 32 publications

Structure of the C-Terminal Domain of the Multifunctional ICP27 Protein from Herpes Simplex Virus 1

Structure of the C-Terminal Domain of the Multifunctional ICP27 Protein from Herpes Simplex Virus 1

The DR1 and DR6 First Exons of Human Herpesvirus 6A Are Not Required for Virus Replication in Culture and Are Deleted in Virus Stocks That Replicate Well in T-Cell Lines

Probing the Interaction between U24 and the SH3 Domain of Fyn Tyrosine Kinase

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