Structural basis of the human Scribble–Vangl2 association in health and disease

How, Jing Yuan; Stephens, Rebecca; Lim, Krystle Y.B.; Humbert, Patrick O.; Kvansakul, Marc

doi:10.1042/bcj20200816

Cited by 13 publications

(15 citation statements)

References 48 publications

(84 reference statements)

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“…β-PIX engages with SCRIB PDZ3 via hydrogen bonds formed by Ser1017 PDZ3 -Asn645 β-PIX , Ser1026 PDZ3 -Trp641 β-PIX , Ser1039 PDZ3 -Glu643 β-PIX and H1071 PDZ3 -T644 β-PIX . In the Scrib PDZ3:NS5_CTN complex, His1071 PDZ3 contacts Ser3412 NS5 in the −2 position in the canonical manner observed in many other PDZ domain complex structures [21][22][23][24]. Interesting, Glu3410 NS5 is able to contact Gln1072 PDZ3 whereas in the PDZ3: β-PIX complex the equivalent Asp642 β-PIX is too short to reach Gln1072 PDZ3 .…”

Section: The Crystal Structures Of Scrib Pdz3:ns5_ctn and Scrib Pdz3mentioning

confidence: 85%

Molecular basis of Tick Born encephalitis virus NS5 mediated subversion of apico-basal cell polarity signalling

Javorsky

Humbert

Kvansakul

2022

Biochemical Journal

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The Scribble (Scrib) protein is a conserved cell polarity regulator with anti-tumorigenic properties. Viruses like the Tick-born encephalitis virus (TBEV) target Scribble to establish a cellular environment supporting viral replication, which is ultimately associated with poor prognosis upon infection. The TBEV NS5 protein has been reported to harbour both an internal as well as a C-terminal PDZ binding motif (PBM), however only the internal PBM was shown to be an interactor with Scribble, with the interaction being mediated via the Scribble PDZ4 domain to antagonize host interferon responses. We examined the NS5 PBM motif interactions with all Scribble PDZ domains using isothermal titration calorimetry, which revealed that the proposed internal PBM did not interact with any Scribble PDZ domains. Instead, the C-terminal PBM of NS5 interacted with Scrib PDZ3. We then established the structural basis of these interactions by determining crystal structures of Scrib PDZ3 bound to the NS5 C-terminal PBM. Our findings provide a structural basis for Scribble PDZ domain and TBEV NS5 interactions and provide a platform to dissect the pathogenesis of TBEV and the role of cell polarity signalling using structure guided approaches.

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Section: The Crystal Structures Of Scrib Pdz3:ns5_ctn and Scrib Pdz3mentioning

confidence: 85%

Molecular basis of Tick Born encephalitis virus NS5 mediated subversion of apico-basal cell polarity signalling

Javorsky

Humbert

Kvansakul

2022

Biochemical Journal

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“…However, in previously solved structures, like SCRIB PDZ2:Vangl2 [ 30 ], this PDZ2 H928 is an important position for an interaction, which could explain the abolished binding seen with the ESKV peptide. SCRIB PDZ3 K1040A showed a weaker interaction with ESEV (22.2 ± 1.1 µM) and ESKV (13.8 ± 0.8 µM) compared to the wild-type SCRIB PDZ3 counterpart (ESEV:13.1 ± 1.6 µM, ESKV:12.1 ± 0.9 µM) ( Table 1 , Figure 5 ).…”

Section: Discussionmentioning

confidence: 99%

“…SCRIB PDZ mutants cDNA PDZ3 H1071A (residues 1002–1093), PDZ4 R1110D (residues 1099–1203), PDZ4 R1116D (residues 1099–1203) and PDZ4 H1170A (residues 1099–1203) were cloned into the pGex-6P3 vector (Bioneer). SCRIB PDZ3 K1040A (residues 1002–1093) was described previously [ 29 ], and all other PDZ mutant constructs were also described previously [ 30 ].…”

Section: Methodsmentioning

confidence: 99%

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Structural Basis of the Avian Influenza NS1 Protein Interactions with the Cell Polarity Regulator Scribble

Javorsky

Humbert

Kvansakul

2022

Viruses

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Scribble is a highly conserved regulator of cell polarity, a process that enables the generation of asymmetry at the cellular and tissue level in higher organisms. Scribble acts in concert with Disc-large (Dlg) and Lethal-2-giant larvae (Lgl) to form the Scribble polarity complex, and its functional dysregulation is associated with poor prognosis during viral infections. Viruses have been shown to interfere with Scribble by targeting Scribble PDZ domains to subvert the network of interactions that enable normal control of cell polarity via Scribble, as well as the localisation of the Scribble module within the cell. The influenza A virus NS1 protein was shown to bind to human Scribble (SCRIB) via its C-terminal PDZ binding motif (PBM). It was reported that the PBM sequence ESEV is a virulence determinant for influenza A virus H5N1 whilst other sequences, such as ESKV, KSEV and RSKV, demonstrated no affinity towards Scribble. We now show, using isothermal titration calorimetry (ITC), that ESKV and KSEV bind to SCRIB PDZ domains and that ESEV unexpectedly displayed an affinity towards all four PDZs and not just a selected few. We then define the structural basis for the interactions of SCRIB PDZ1 domain with ESEV and ESKV PBM motifs, as well as SCRIB PDZ3 with the ESKV PBM motif. These findings will serve as a platform for understanding the role of Scribble PDZ domains and their interactions with different NS1 PBMs and the mechanisms that mediate cell polarity within the context of the pathogenesis of influenza A virus.

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“…SCRIB is a component of the apical–basal cell polarity machinery; thus, it may serve as a communication hub for polarity and as a coordinator of motility on both planes in cancer cells [ 35 ]. The interaction of VANGL tetraspanins and SCRIB has been mapped to involve the carboxyterminal PBM (PDZ binding motif) domain of the former with the PDZ (PSD95-Discs large-ZO-1) domains of the latter [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

Molecular Alterations and Putative Therapeutic Targeting of Planar Cell Polarity Proteins in Breast Cancer

Voutsadakis

2023

JCM

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Background: Treatment and outcomes of breast cancer, one of the most prevalent female cancers, have improved in recent decades. However, metastatic breast cancer remains incurable in most cases, and new therapies are needed to ameliorate prognosis. Planar cell polarity (PCP) is a characteristic of epithelial cells that form layers and is integral to the communication of these cells with neighboring cells. Dysfunction of PCP is observed in cancers and may confer a targetable vulnerability. Methods: The breast cancer cohorts from The Cancer Genome Atlas (TCGA) and the METABRIC study were interrogated for molecular alterations in genes of the PCP pathway. The groups with the most prevalent alterations were characterized, and survival was compared with counterparts not possessing PCP alterations. Breast cancer cell lines with PCP alterations from the Cancer Cell Line Encyclopedia (CCLE) were interrogated for sensitivity to drugs affecting PCP. Results: Among genes of the PCP pathway, VANGL2, NOS1AP and SCRIB display amplifications in a sizable minority of breast cancers. Concomitant up-regulation at the mRNA level can be observed mostly in basal cancers, but it does not correlate well with the amplification status of the genes, as it can also be observed in non-amplified cases. In an exploration of cell line models, two of the four breast cancer cell line models with amplifications in VANGL2, NOS1AP and SCRIB display sensitivity to drugs inhibiting acyl-transferase porcupine interfering with the WNT pathway. This sensitivity suggests a possible therapeutic role of these inhibitors in cancers bearing the amplifications. Conclusion: Molecular alterations in PCP genes can be observed in breast cancers with a predilection for the basal sub-type. An imperfect correlation of copy number alterations with mRNA expression suggests that post-translational modifications are important in PCP regulation. Inhibitors of acyl-transferase porcupine may be rational candidates for combination therapy development in PCP-altered breast cancers.

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Structural basis of the human Scribble–Vangl2 association in health and disease

Cited by 13 publications

References 48 publications

Molecular basis of Tick Born encephalitis virus NS5 mediated subversion of apico-basal cell polarity signalling

Molecular basis of Tick Born encephalitis virus NS5 mediated subversion of apico-basal cell polarity signalling

Structural Basis of the Avian Influenza NS1 Protein Interactions with the Cell Polarity Regulator Scribble

Molecular Alterations and Putative Therapeutic Targeting of Planar Cell Polarity Proteins in Breast Cancer

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