The N-terminal Proline Hinge Motif Controls the Structure of Bovine Herpesvirus 1-encoded Inhibitor of the Transporter Associated with Antigen Processing Required for its Immunomodulatory Function

Graul, Małgorzata; Karska, Natalia; Wąchalska, Magda; Krupa, Paweł; Ślusarz, Magdalena J.; Lubocki, Marcin; Bieńkowska-Szewczyk, Krystyna; Rodziewicz‐Motowidło, Sylwia; Sieradzan, Adam K.; Lipińska, Andrea D.

doi:10.1016/j.jmb.2023.167964

Cited by 8 publications

(20 citation statements)

References 49 publications

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“…The structure of this protein in the ER membrane is very similar to that in the POPC membrane and that was described in our earlier publication (Graul et al, 2023;Karska et al, 2019). Similarly, identical data from the dynamics of the UL49.5 protein in the ER and in the POPC membrane (Graul et al, 2023) was obtained in the analysis of psi and phi torsion angles (Figure S9A and C). It can be seen that in three regions these angles correspond to the helical structure.…”

Section: Analysis Of 3d Structure Of Nhsv and Chsv Peptides Obtained ...supporting

confidence: 82%

“…However, it must be admitted that the fluctuations of this part of the protein from both viruses are similar. Interestingly, both proteins in the Nterminal part of the transmembrane helix contain Pro residues which, as we showed in our recent work (Graul et. al, 2023), are crucial for the biological activity of the BoHV-1-encoded UL49.5 protein .…”

Section: Analysis Of 3d Structure Of Nhsv and Chsv Peptides Obtained ...supporting

confidence: 76%

“…The rest of the protein (transmembrane fragment) exhibited considerably lower mobility. We obtained identical results for this protein during molecular dynamics in the POPC membrane (Graul. et al, 2023).…”

Section: Analysis Of 3d Structure Of Nhsv and Chsv Peptides Obtained ...mentioning

confidence: 55%

“…All the peptides (N.HSV, C.HSV, TMC.HSV and TMC.HSV.KKK) were synthesized using the standard solid-phase synthesis technique (Liberty Blue, CEM Corporation, USA). The synthesis and purification of peptides was carried out according to the procedures described in our previous publications (Karska et al 2019, Karska et al 2021Graul et al 2023).…”

Section: Peptide Synthesis and Purificationmentioning

confidence: 99%

“…At the last step, three 1000ns trajectories of production runs were performed for two variants of UL49.5 protein: with uncharged and charged H67. For sake of comparison, MD simulation in the same lipid bilayer model was run for UL49.5 protein from BoHV-1 virus in the same scheme (Graul et al, 2023).…”

Section: Simulations Of Ul495 In Theer Membrane Modelmentioning

confidence: 99%

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Why does the UL49.5 of herpes simplex 1 virus fail to inhibit the TAP-dependent antigen presentation?

Rodziewicz‐Motowidło

Krupa

Karska

et al. 2023

Preprint

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Herpes simplex virus type 1 (HSV-1) is a well-studied herpesvirus that causes a number of human diseases. The HSV-1, like other herpesviruses, produces transmembrane glycoprotein N (gN / UL49.5 protein). Although this protein is conserved throughout the herpesvirus family, little is known about its function in HSV-1. The amino-acid sequence and length of UL49.5 proteins differ between herpesvirus species. It is, therefore, crucial to determine whether and to what extent the spatial structure of UL49.5 orthologs that are TAP inhibitors (i.e., of BoHV-1 virus) differs from that of non-TAP inhibitors (i.e., of HSV-1 virus). As a result, the primary goal of our study was to examine the 3D structure of HSV-1-encoded UL49.5 protein in an advanced model of the endoplasmic reticulum (ER) membrane. Circular dichroism (CD), 2D nuclear magnetic resonance (NMR), and multiple-microsecond all-atom molecular dynamics (MD) simulations in the ER membrane mimetic environment were used to determine the final structure of the HSV-1 UL49.5 protein. According to our findings, the N-terminus of HSV-1 UL49.5 adopts a highly flexible, unordered structure in the extracellular part due to the presence of a large number of Pro and Gly residues. In contrast to the UL49.5 protein from BoHV-1, the transmembrane region of HSV-1-encoded UL49.5 is formed by a single long transmembrane -helix, rather than two helices oriented perpendicularly, while the cytoplasmic part of the protein (C-terminus) has a short unordered structure. Our findings provide experimental structural information on HSV-1-encoded UL49.5 protein and structure-based insight into its lack of biological activity in inhibiting the TAP-independent antigen presentation pathway.

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Section: Analysis Of 3d Structure Of Nhsv and Chsv Peptides Obtained ...supporting

confidence: 82%

Section: Analysis Of 3d Structure Of Nhsv and Chsv Peptides Obtained ...supporting

confidence: 76%

Section: Analysis Of 3d Structure Of Nhsv and Chsv Peptides Obtained ...mentioning

confidence: 55%

Section: Peptide Synthesis and Purificationmentioning

confidence: 99%

Section: Simulations Of Ul495 In Theer Membrane Modelmentioning

confidence: 99%

See 3 more Smart Citations

Why does the UL49.5 of herpes simplex 1 virus fail to inhibit the TAP-dependent antigen presentation?

Rodziewicz‐Motowidło

Krupa

Karska

et al. 2023

Preprint

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An intrinsic network of polar interactions is responsible for binding of UL49.5 C‐degron by the CRL2^KLHDC3 ubiquitin ligase

Ślusarz,

Lipińska

2023

Proteins

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Bovine herpesvirus type 1 (BoHV‐1) is a pathogen of cattle responsible for infectious bovine rhinotracheitis. The BoHV‐1 UL49.5 is a transmembrane protein that binds to the transporter associated with antigen processing (TAP) and downregulates cell surface expression of the antigenic peptide complexes with the major histocompatibility complex class I (MHC‐I). KLHDC3 is a kelch domain‐containing protein 3 and a substrate receptor of a cullin2‐RING (CRL2) E3 ubiquitin ligase. Recently, it has been identified that CRL2KLHDC3 is responsible for UL49.5‐triggered TAP degradation via a C‐degron pathway and the presence of the degron sequence does not lead to the degradation of UL49.5 itself. The molecular modeling of KLHDC3 in complexes with four UL49.5 C‐terminal decapeptides (one native protein and three mutants) revealed their activity to be closely correlated with the conformation which they adopt in KLHDC3 binding cleft. To analyze the interaction between UL49.5 and KLHDC3 in detail, in this work a total of 3.6 μs long molecular dynamics simulations have been performed. The complete UL49.5‐KLHDC3 complexes were embedded into the fully hydrated all‐atom lipid membrane model with explicit water molecules. The network of polar interactions has been proposed to be responsible for the recognition and binding of the degron in KLHDC3. The interaction network within the binding pocket appeared to be very similar between two CRL2 substrate receptors: KLHDC3 and KLHDC2.

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Why does the herpes simplex 1 virus-encoded UL49.5 protein fail to inhibit the TAP-dependent antigen presentation?

Karska,

Zhukov,

Lipińska

et al. 2023

Biochimica et Biophysica Acta (BBA) - Biomembranes

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The N-terminal Proline Hinge Motif Controls the Structure of Bovine Herpesvirus 1-encoded Inhibitor of the Transporter Associated with Antigen Processing Required for its Immunomodulatory Function

Cited by 8 publications

References 49 publications

Why does the UL49.5 of herpes simplex 1 virus fail to inhibit the TAP-dependent antigen presentation?

Why does the UL49.5 of herpes simplex 1 virus fail to inhibit the TAP-dependent antigen presentation?

An intrinsic network of polar interactions is responsible for binding of UL49.5 C‐degron by the CRL2^KLHDC3 ubiquitin ligase

Why does the herpes simplex 1 virus-encoded UL49.5 protein fail to inhibit the TAP-dependent antigen presentation?

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The N-terminal Proline Hinge Motif Controls the Structure of Bovine Herpesvirus 1-encoded Inhibitor of the Transporter Associated with Antigen Processing Required for its Immunomodulatory Function

Cited by 8 publications

References 49 publications

Why does the UL49.5 of herpes simplex 1 virus fail to inhibit the TAP-dependent antigen presentation?

Why does the UL49.5 of herpes simplex 1 virus fail to inhibit the TAP-dependent antigen presentation?

An intrinsic network of polar interactions is responsible for binding of UL49.5 C‐degron by the CRL2KLHDC3 ubiquitin ligase

Why does the herpes simplex 1 virus-encoded UL49.5 protein fail to inhibit the TAP-dependent antigen presentation?

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An intrinsic network of polar interactions is responsible for binding of UL49.5 C‐degron by the CRL2^KLHDC3 ubiquitin ligase