Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Nicastrin-like, a Novel Transmembrane Protein from Trypanosoma cruzi Associated to the Flagellar Pocket

Version 1 : Received: 26 June 2021 / Approved: 28 June 2021 / Online: 28 June 2021 (14:55:42 CEST)

A peer-reviewed article of this Preprint also exists.

Lechuga, G.C.; Napoleão-Pêgo, P.; Gomes, L.R.; da Matta Durans, A.; Provance, D.W., Jr.; De-Simone, S.G. Nicastrin-Like, a Novel Transmembrane Protein from Trypanosoma cruzi Associated to the Flagellar Pocket. Microorganisms 2021, 9, 1750. Lechuga, G.C.; Napoleão-Pêgo, P.; Gomes, L.R.; da Matta Durans, A.; Provance, D.W., Jr.; De-Simone, S.G. Nicastrin-Like, a Novel Transmembrane Protein from Trypanosoma cruzi Associated to the Flagellar Pocket. Microorganisms 2021, 9, 1750.

Journal reference: Microorganisms 2021, 9, 1750
DOI: 10.3390/microorganisms9081750

Abstract

Nicastrin (NICT) is a transmembrane protein physically associated with the polytypical aspartyl protease presenilin that plays a vital role in the correct localization and stabilization of presenilin to the membrane-bound γ-secretase complex. This complex is involved in the regulation of a wide range of cellular events including cell signaling and the regulation of endocytosed membrane proteins for their trafficking and protein processing. Mehtods: In Trypanosoma cruzi, the causal agent of the Chagas disease, an NICT-like protein (Tc/NICT) was identified with a short C-terminus orthologous to the human protein, a large ectodomain (ECD) with numerous glycosylation sites and a single core transmembrane domain containing a putative TM-domain (457GSVGA461) important for the γ-secretase complex activity. Results: Using the Spot-synthesis strategy with Chagasic patient sera, five extracellular epitopes were identified and synthetic forms were used to generate rabbit anti-Tc/NICT polyclonal serum that recognized a ~72-kDa molecule in immunoblots of T. cruzi epimastigote extracts. Confocal microscopy suggests that Tc/NICT is localized in the flagellar pocket, which is consistent with data from our previous studies with a T. cruzi presenilin-like protein. Phylogenetically, Tc/NICT was localized within a subgroup with the T. rangeli protein that are clearly detached from the other Trypanosomatidae such as T. brucei. These results, together with a comparative analysis of the selected peptide sequence regions between the T. cruzi and mammalian proteins suggest a divergence from the human NICT that might be relevant to Chagas disease pathology. As a whole, our data show that an NICT-like protein is expressed in the infective and replicative stages of T. cruzi and may be considered further evidence for a γ-secretase complex in trypanosomatids.

Keywords

Trypanosoma cruzi; Presenilin; Nicastrin; γ-secretase; transmembrane motif; B-cell epitope; Spot synthesis; type I transmembrane glycoprotein; vesicular trafficking; flagellar pocket

Subject

LIFE SCIENCES, Biochemistry

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