Micropeptide hetero-oligomerization adds complexity to the calcium pump regulatory network

Phillips, Taylor A.; Hauck, G; Pribadi, Marsha P.; Cho, Ellen E.; Cleary, Sean R.; Robia, Seth L.

doi:10.1016/j.bpj.2022.12.014

Cited by 3 publications

(2 citation statements)

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“…We utilized AP-FRET and confirmed physical interaction between E protein, regulins and SERCA2b. Our results on regulin heterodimerization are in good agreement with a recent study on regulins with FRET-based experiments (15,25). Most importantly, our experiments demonstrated an interaction between E protein and SERCA confirming high-throughput assays, which identified this interaction (32,33).…”

Section: Discussionsupporting

confidence: 92%

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SARS-CoV-2 Envelope protein alters calcium signaling via SERCA interactions

Berta

Tordai

Lukacs

et al. 2023

Preprint

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The clinical management of severe COVID-19 cases is not yet well resolved. Therefore, it is important to identify and characterize cell signaling pathways involved in virus pathogenesis that can be targeted therapeutically. Envelope (E) protein is a structural protein of the virus, which is known to be highly expressed in the infected host cell and is a key virulence factor, however, its role is poorly characterized. The E protein is a single-pass transmembrane protein that can assemble into a pentamer forming a viroporin, perturbing Ca2+ homeostasis. Because it is structurally similar to regulins such as, for example, phospholamban, that regulate the sarco/endoplasmic reticulum calcium ATPases (SERCA), we investigated whether the SARS-CoV-2 E protein affects the SERCA system as an exoregulin. Using FRET experiments we demonstrate that E protein can form oligomers with regulins, and thus can alter the monomer/multimer regulin ratio and consequently influence their interactions with SERCAs. We also confirmed that a direct interaction between E protein and SERCA2b results in a decrease in SERCA-mediated ER Ca2+ reload. Structural modeling and molecular dynamics of the complexes indicates an overlapping interaction site for E protein and endogenous regulins. Our results reveal novel links in the host-virus interaction network that play an important role in viral pathogenesis and may provide a new therapeutic target for managing severe inflammatory responses induced by SARS-CoV-2.

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Section: Discussionsupporting

confidence: 92%

“…Oligomer formation was also observed for the other regulins, and these regulins were also bound to SERCA in a monomeric form (15). In addition, different regulins hetero-oligomerize with each other and this may lead to further fine-tuning of their effects on SERCA-dependent calcium transport (25).…”

Section: Introductionmentioning

confidence: 83%