Trypanosomatid Flagellar Pocket from Structure to Function

Halliday, Clare; Neto, Artur Leonel de Castro; Alcântara, Carolina L.; Cunha-e-Silva, Narcisa L.; Vaughan, Sue; Sunter, Jack D.

doi:10.1016/j.pt.2020.11.005

Cited by 32 publications

(36 citation statements)

References 92 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The cell membrane of Leishmania is reinforced by a longitudinal subpellicular layer of microtubules [ 39 ]. This confines all the membrane traffic to a small membrane area devoid of microtubules, the flagellar pocket [ 40 ]. In addition, it is endowed with a strong proteolytic armamentarium not only in the surface, but also in lysosomal enzymes, especially in the amastigote form of those species, as L. pifanoi , belonging to the mexicana complex [ 41 , 42 ].…”

Section: Resultsmentioning

confidence: 99%

Hybrid Cyclobutane/Proline-Containing Peptidomimetics: The Conformational Constraint Influences Their Cell-Penetration Ability

Illa

Ospina

Sánchez-Aparicio

et al. 2021

IJMS

View full text Add to dashboard Cite

A new family of hybrid β,γ-peptidomimetics consisting of a repetitive unit formed by a chiral cyclobutane-containing trans-β-amino acid plus a Nα-functionalized trans-γ-amino-l-proline joined in alternation were synthesized and evaluated as cell penetrating peptides (CPP). They lack toxicity on the human tumoral cell line HeLa, with an almost negligible cell uptake. The dodecapeptide showed a substantial microbicidal activity on Leishmania parasites at 50 µM but with a modest intracellular accumulation. Their previously published γ,γ-homologues, with a cyclobutane γ-amino acid, showed a well-defined secondary structure with an average inter-guanidinium distance of 8–10 Å, a higher leishmanicidal activity as well as a significant intracellular accumulation. The presence of a very rigid cyclobutane β-amino acid in the peptide backbone precludes the acquisition of a defined conformation suitable for their cell uptake ability. Our results unveiled the preorganized charge-display as a relevant parameter, additional to the separation among the charged groups as previously described. The data herein reinforce the relevance of these descriptors in the design of CPPs with improved properties.

show abstract

Section: Resultsmentioning

confidence: 99%

Hybrid Cyclobutane/Proline-Containing Peptidomimetics: The Conformational Constraint Influences Their Cell-Penetration Ability

Illa

Ospina

Sánchez-Aparicio

et al. 2021

IJMS

View full text Add to dashboard Cite

show abstract

“…brucei , the FAZ and the FP participate to this strict segregation order as they are both required for the correct positioning of these organelles before (and after) cytokinesis [ 12 , 38 , 39 ]; moreover, FP duplication is part of the sequence of coordinated events required for normal cytokinesis to proceed [ 38 , 40 ]. In Leishmania , FP biogenesis is ill-known, but the duplication of the FP is linked to the duplication and segregation of the kinetoplast [ 2 , 26 ]. Thus, a delay or perturbation of FP biogenesis may lead to the anomalies observed in kinetoplast segregation, and to the disruption of cell division.…”

Section: Discussionmentioning

confidence: 99%

“…At the base of the flagellum is an invagination of the cell membrane called the flagellar pocket (FP), which is the only site for endocytosis and exocytosis. The FP has key roles in several cellular processes, including flagellum assembly, cell shape, cell division and immune evasion [ 2 ] hence is crucial for parasite pathogenicity. The FP comprises two regions: the bulbous lumen, immediately anterior/distal to the basal body, and the distal FP neck [ 3 ] (see schematic in Fig 1H ).…”

Section: Introductionmentioning

confidence: 99%

The kinesin of the flagellum attachment zone in Leishmania is required for cell morphogenesis, cell division and virulence in the mammalian host

et al. 2021

View full text Add to dashboard Cite

Leishmania parasites possess a unique and complex cytoskeletal structure termed flagellum attachment zone (FAZ) connecting the base of the flagellum to one side of the flagellar pocket (FP), an invagination of the cell body membrane and the sole site for endocytosis and exocytosis. This structure is involved in FP architecture and cell morphogenesis, but its precise role and molecular composition remain enigmatic. Here, we characterized Leishmania FAZ7, the only known FAZ protein containing a kinesin motor domain, and part of a clade of trypanosomatid-specific kinesins with unknown functions. The two paralogs of FAZ7, FAZ7A and FAZ7B, display different localizations and functions. FAZ7A localizes at the basal body, while FAZ7B localizes at the distal part of the FP, where the FAZ structure is present in Leishmania. While null mutants of FAZ7A displayed normal growth rates, the deletion of FAZ7B impaired cell growth in both promastigotes and amastigotes of Leishmania. The kinesin activity is crucial for its function. Deletion of FAZ7B resulted in altered cell division, cell morphogenesis (including flagellum length), and FP structure and function. Furthermore, knocking out FAZ7B induced a mis-localization of two of the FAZ proteins, and disrupted the molecular organization of the FP collar, affecting the localization of its components. Loss of the kinesin FAZ7B has important consequences in the insect vector and mammalian host by reducing proliferation in the sand fly and pathogenicity in mice. Our findings reveal the pivotal role of the only FAZ kinesin as part of the factors important for a successful life cycle of Leishmania.

show abstract

“…No particularly extraordinary endomembranes have been noted. One unique feature of the kinetoplastids is that the membrane trafficking at the plasma membrane is primarily restricted to the flagellar pocket [ 21 ]. The flagellar pocket is an invagination of the plasma membrane where the flagellum emerges from the cell.…”

Section: Kinetoplastidsmentioning

confidence: 99%

Unique Endomembrane Systems and Virulence in Pathogenic Protozoa

Wiser

2021

Life

View full text Add to dashboard Cite

Virulence in pathogenic protozoa is often tied to secretory processes such as the expression of adhesins on parasite surfaces or the secretion of proteases to assisted in tissue invasion and other proteins to avoid the immune system. This review is a broad overview of the endomembrane systems of pathogenic protozoa with a focus on Giardia, Trichomonas, Entamoeba, kinetoplastids, and apicomplexans. The focus is on unique features of these protozoa and how these features relate to virulence. In general, the basic elements of the endocytic and exocytic pathways are present in all protozoa. Some of these elements, especially the endosomal compartments, have been repurposed by the various species and quite often the repurposing is associated with virulence. The Apicomplexa exhibit the most unique endomembrane systems. This includes unique secretory organelles that play a central role in interactions between parasite and host and are involved in the invasion of host cells. Furthermore, as intracellular parasites, the apicomplexans extensively modify their host cells through the secretion of proteins and other material into the host cell. This includes a unique targeting motif for proteins destined for the host cell. Most notable among the apicomplexans is the malaria parasite, which extensively modifies and exports numerous proteins into the host erythrocyte. These modifications of the host erythrocyte include the formation of unique membranes and structures in the host erythrocyte cytoplasm and on the erythrocyte membrane. The transport of parasite proteins to the host erythrocyte involves several unique mechanisms and components, as well as the generation of compartments within the erythrocyte that participate in extraparasite trafficking.

show abstract

Trypanosomatid Flagellar Pocket from Structure to Function

Cited by 32 publications

References 92 publications

Hybrid Cyclobutane/Proline-Containing Peptidomimetics: The Conformational Constraint Influences Their Cell-Penetration Ability

Hybrid Cyclobutane/Proline-Containing Peptidomimetics: The Conformational Constraint Influences Their Cell-Penetration Ability

The kinesin of the flagellum attachment zone in Leishmania is required for cell morphogenesis, cell division and virulence in the mammalian host

Unique Endomembrane Systems and Virulence in Pathogenic Protozoa

Contact Info

Product

Resources

About