The Unusual Fold of Herpes Simplex Virus 1 UL21, a Multifunctional Tegument Protein

Metrick, C.M.; Chadha, Pooja; Heldwein, Ekaterina E.

doi:10.1128/jvi.03516-14

Cited by 21 publications

(38 citation statements)

References 34 publications

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“…Consistent with this, single-amino-acid changes within the CTD of full-length UL16 also activate binding to UL11, although they do not stimulate binding to gE and VP22 (12,36,37). Moreover, UL16 binds directly to UL21, and although the sites of contact are unknown, this interaction also activates binding to UL11 but, again, not to gE (26,(45)(46)(47)(48)(49)(50). Thus, it seems that UL16 has at least two functional domains: an NTD that mediates binding to partners on the membrane and a CTD that regulates those interactions in a complicated manner (36).…”

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confidence: 52%

Domain Interaction Studies of Herpes Simplex Virus 1 Tegument Protein UL16 Reveal Its Interaction with Mitochondria

Chadha

Sarfo

Zhang

et al. 2017

J Virol

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The UL16 tegument protein of herpes simplex virus 1 (HSV-1) is conserved among all herpesviruses and plays many roles during replication. This protein has an N-terminal domain (NTD) that has been shown to bind to several viral proteins, including UL11, VP22, and glycoprotein E, and these interactions are negatively regulated by a C-terminal domain (CTD). Thus, in pairwise transfections, UL16 binding is enabled only when the CTD is absent or altered. Based on these results, we hypothesized that direct interactions occur between the NTD and the CTD. Here we report that the separated and coexpressed functional domains of UL16 are mutually responsive to each other in transfected cells and form complexes that are stable enough to be captured in coimmunoprecipitation assays. Moreover, we found that the CTD can associate with itself. To our surprise, the CTD was also found to contain a novel and intrinsic ability to localize to specific spots on mitochondria in transfected cells. Subsequent analyses of HSV-infected cells by immunogold electron microscopy and live-cell confocal imaging revealed a population of UL16 that does not merely accumulate on mitochondria but in fact makes dynamic contacts with these organelles in a time-dependent manner. These findings suggest that the domain interactions of UL16 serve to regulate not just the interaction of this tegument protein with its viral binding partners but also its interactions with mitochondria. The purpose of this novel interaction remains to be determined. IMPORTANCEThe HSV-1-encoded tegument protein UL16 is involved in multiple events of the virus replication cycle, ranging from virus assembly to cell-cell spread of the virus, and hence it can serve as an important drug target. Unfortunately, a lack of both structural and functional information limits our understanding of this protein. The discovery of domain interactions within UL16 and the novel ability of UL16 to interact with mitochondria in HSV-infected cells lays a foundational framework for future investigations aimed at deciphering the structure and function of not just UL16 of HSV-1 but also its homologs in other herpesviruses.KEYWORDS domains, HSV-1, herpes simplex virus, mitochondria, tegument, UL16 H erpes simplex virus 1 (HSV-1) contains a 373-amino-acid tegument protein, UL16 (Fig. 1), which is conserved among all families of herpesviruses (1-15). Encoded by the late-expressing 16th open reading frame in the unique long segment of the viral genome, UL16 initially localizes to both the nucleus and the cytoplasm of the infected cell but later accumulates in the cytoplasm (4, 16). There, a population of UL16 is found to be stably associated with an unknown partner on cytoplasmic capsids (16,17), where it plays a role in envelopment by providing bridging functions via its interaction with at least three viral membrane proteins: UL11, glycoprotein E (gE), and VP22 (12, 18-43). Thus, UL16-null mutants produce only 1/10 the number of wild-type virions (1, 12), and

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confidence: 52%

Domain Interaction Studies of Herpes Simplex Virus 1 Tegument Protein UL16 Reveal Its Interaction with Mitochondria

Chadha

Sarfo

Zhang

et al. 2017

J Virol

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“…To uncover additional conservation patterns within UL21C, we performed evolutionary trace analysis (ETA), a method of identifying functionally important residues on the basis of their resistance to mutations over evolutionary time (44), as has been done for herpesvirus proteins UL25 (45), UL37N (46), and UL21N (21). After an evolutionary tree (Fig.…”

Section: Ul21 Is Composed Of Two Stable Domainsmentioning

confidence: 99%

“…We also describe the unanticipated ability of UL21 to bind RNA, which may hint at a yet unexplored function. In combination with the previously determined structure of the N-terminal domain of UL21 (UL21N) (21), the novel dragonfly-shaped structure of UL21C enables structure-guided mutagenesis and functional exploration of the multiple roles of UL21 in the replication and pathogenesis of alphaherpesviruses.…”

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confidence: 99%

“…UL21 is a tegument protein that is conserved among the members of the alphaherpesvirus subfamily (20,21), with sequence identity ranging from 27 to 84% and sequence similarity ranging from 57 to 94%. Beta-and gammaherpesviruses encode positional homologs of UL21 within their genomes (e.g., human cytomegalovirus [HCMV] UL87 and Kaposi's sarcoma-associated herpesvirus [KSHV] ORF24), but in the absence of obvious sequence similarity, it is not clear whether these proteins share functions.…”

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confidence: 99%

“…Finally, some tegument proteins can bind RNA. For example, UL47 (VP13/14), one of the most abundant components of the tegument in alphaherpesviruses (15), is also a nucleocytoplasmic shuttle (16, 17) that preferentially binds single-stranded polyadenylated RNAs (18), including some viral mRNAs, and may help incorporate them into nascent virions (19).UL21 is a tegument protein that is conserved among the members of the alphaherpesvirus subfamily (20,21), with sequence identity ranging from 27 to 84% and sequence similarity ranging from 57 to 94%. Beta-and gammaherpesviruses encode positional homologs of UL21 within their genomes (e.g., human cytomegalovirus [HCMV] UL87 and Kaposi's sarcoma-associated herpesvirus [KSHV] ORF24), but in the absence of obvious sequence similarity, it is not clear whether these proteins share functions.…”

mentioning

confidence: 99%

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Novel Structure and Unexpected RNA-Binding Ability of the C-Terminal Domain of Herpes Simplex Virus 1 Tegument Protein UL21

Metrick

Heldwein

2016

J Virol

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Proteins forming the tegument layers of herpesviral virions mediate many essential processes in the viral replication cycle, yet few have been characterized in detail. UL21 is one such multifunctional tegument protein and is conserved among alphaherpesviruses. While UL21 has been implicated in many processes in viral replication, ranging from nuclear egress to virion morphogenesis to cell-cell spread, its precise roles remain unclear. Here we report the 2.7-Å crystal structure of the C-terminal domain of herpes simplex virus 1 (HSV-1) UL21 (UL21C), which has a unique ␣-helical fold resembling a dragonfly. Analysis of evolutionary conservation patterns and surface electrostatics pinpointed four regions of potential functional importance on the surface of UL21C to be pursued by mutagenesis. In combination with the previously determined structure of the N-terminal domain of UL21, the structure of UL21C provides a 3-dimensional framework for targeted exploration of the multiple roles of UL21 in the replication and pathogenesis of alphaherpesviruses. Additionally, we describe an unanticipated ability of UL21 to bind RNA, which may hint at a yet unexplored function. IMPORTANCEDue to the limited genomic coding capacity of viruses, viral proteins are often multifunctional, which makes them attractive antiviral targets. Such multifunctionality, however, complicates their study, which often involves constructing and characterizing null mutant viruses. Systematic exploration of these multifunctional proteins requires detailed road maps in the form of 3-dimensional structures. In this work, we determined the crystal structure of the C-terminal domain of UL21, a multifunctional tegument protein that is conserved among alphaherpesviruses. Structural analysis pinpointed surface areas of potential functional importance that provide a starting point for mutagenesis. In addition, the unexpected RNA-binding ability of UL21 may expand its functional repertoire. The structure of UL21C and the observation of its RNA-binding ability are the latest additions to the navigational chart that can guide the exploration of the multiple functions of UL21. Due to the limited genomic coding capacity of viruses, viral proteins are often multifunctional. Although herpesviruses have relatively large double-stranded DNA (dsDNA) genomes, they encode a number of proteins that mediate more than one unrelated function. A notable example is proteins located within the tegument, a thick protein layer located between the nucleocapsid and the envelope of a herpesviral virion. Although tegument proteins play structural roles, many have additional functions unrelated to viral assembly. For example, while UL36 (1, 2) and UL37 (3, 4) are required for proper viral assembly, both proteins are also necessary for efficient capsid trafficking (5-7), and UL36 additionally harbors deubiquitinating activity in its N terminus (8). UL48 serves as a hub of tegumentation and is necessary for herpes simplex virus 1 (HSV-1) morphogenesis (9-11); it is also known as ...

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Herpes simplex virus 1 protein pUL21 alters ceramide metabolism by activating the interorganelle transport protein CERT

Benedyk¹,

Connor²,

Caroe³

et al. 2022

Journal of Biological Chemistry

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The Unusual Fold of Herpes Simplex Virus 1 UL21, a Multifunctional Tegument Protein

Cited by 21 publications

References 34 publications

Domain Interaction Studies of Herpes Simplex Virus 1 Tegument Protein UL16 Reveal Its Interaction with Mitochondria

Domain Interaction Studies of Herpes Simplex Virus 1 Tegument Protein UL16 Reveal Its Interaction with Mitochondria

Novel Structure and Unexpected RNA-Binding Ability of the C-Terminal Domain of Herpes Simplex Virus 1 Tegument Protein UL21

Herpes simplex virus 1 protein pUL21 alters ceramide metabolism by activating the interorganelle transport protein CERT

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