MPP5 binds SARS-CoV-1 E pentamer

Stable Identifier
Reaction [binding]
Homo sapiens
Related Species
Human SARS coronavirus
Locations in the PathwayBrowser
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MAGUK p55 subfamily member 5 (MPP5, also known as PALS1), a tight junction‑associated protein, is a member of the CRUMBS3:MPP5:PATJ polarity complex, which is crucial for the establishment and maintenance of epithelial polarity in mammals. MPP5 has multiple protein‑protein interaction domains including a PSD‑95/Dlg/ZO‑1 (PDZ) domain. A functional PDZ domain‑binding motif has been identified at the carboxy‑terminus of severe acute respiratory syndrome coronavirus type 1 (SARS‑CoV‑1) envelope (E) protein (Teoh KT et al. 2010; Jimenez‑Guardeño JM et al. 2014). SARS‑CoV‑1 E is abundantly expressed inside the infected cell and is involved in pathogenic viral mechanisms (Venkatagopalan P et al. 2015). Infection of mice with recombinant viruses lacking an E protein PDZ domain‑binding motif was associated with decreased expression of inflammatory cytokines and increased survival (Jimenez‑Guardeño JM et al. 2014). SARS‑CoV‑1 E was found to interfere with host PDZ‐dependent interactions of MPP5, thus favoring viral replication (Teoh KT et al. 2010). Coimmunoprecipitation and pull‑down assays showed that the viral E protein interacted with MPP5 in human embryonic kidney 293T (HEK293T) and African green monkey kidney Vero E6 cells (Teoh KT et al. 2010). The last four carboxy‑terminal amino acids (DLLV) of E interacted with the PDZ domain of MPP5 (Teoh KT et al. 2010). Immunofluorescence assay showed that MPP5 was mainly localized at cell‑cell junctions in monolayers of non infected Vero E6 cells, while the binding of SARS‑CoV‑1 E to MPP5 (PALS1) redistributed MPP5 from the tight junctions of the lung epithelium to the ER‑Golgi intermediate compartment (ERGIC) where E assembles in SARS‑CoV‑1‑infected cells (Teoh KT et al. 2010). Ectopic expression of E in Madin‑Darby canine kidney II (MDCKII) epithelial cells altered cyst morphogenesis, delayed formation of tight junctions, affected cell polarity, and modified the subcellular distribution of PALS1, in a PDZ‑binding motif‑dependent manner (Teoh KT et al. 2010). These findings suggest that SARS‑CoV‑1 E interacts with MPP5 (PALS1) and most likely retains MPP5 at the virus assembly site in mammalian cells. However, the relevance of this interaction during virus infection and its impact on virulence in vivo was not tested.

A sequence comparison of the E proteins of the pathogenic human CoVs, SARS‑CoV‑1, MERS‑CoV, and SARS‑CoV‑2, demonstrated a very high sequence similarity between SARS‑CoV‑1 E and SARS‑CoV‑2 E (Grifoni A et al. 2020; Schoeman D & Fielding BC 2020; Hassan SS et al. 2020). This similarity is not shared with the MERS‑CoV E protein (Schoeman D & Fielding BC 2020). In silico modelling analyses of E proteins conformation and docking suggested a strengthened binding of SARS‑CoV‑2 E protein with the tight junction‑associated MPP5 protein (De Maio F et al. 2020). Equilibrium and kinetic binding experiments between peptides mimicking the E protein of SARS‑CoV‑1 and SARS‑CoV‑2 and the PDZ domain of MPP5 further support that the binding affinity of SARS‑CoV‑2 E protein for MPP5 is increased compared to SARS-CoV-1 E protein (Toto A et al. 2020).

Literature References
PubMed ID Title Journal Year
20861307 The SARS coronavirus E protein interacts with PALS1 and alters tight junction formation and epithelial morphogenesis

Margolis, B, Liu, CJ, Teoh, KT, Bruzzone, R, Nal, B, Peiris, JS, Chan, WL, Siu, YL, Schlüter, MA

Mol. Biol. Cell 2010
Orthologous Events
Name Identifier Synonyms
severe acute respiratory syndrome DOID:2945 SARS-CoV infection, SARS
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