| Abstract | dc.description.abstract | Calreticulin (CRT) is a multifaceted protein of 45k Da, early
discovered as a receptor of the collagen-like regions of the complement
C1q protein and better known as an ER chaperone protein, essential in calcium metabolism. Various implications in cancer,
early development and immunology were discovered more
recently for CRT, as well as its role as a dominant “eat-me” prophagocytic
signal. Intriguingly, cell-surface exposure/secretion of
CRT is among the infective strategies used by several human parasites.
We focused on the CRTs from Trypanosoma cruzi (TcCRT) and
Entamoeba histolytica (EhCRT).
Analysis of the interaction between C1q and both parasite CRTs
provided several lines of evidence for the main contribution of
the C1q and CRT globular regions, at least in vitro. Because of the
inherent flexibility of CRTs, their analysis by X-ray crystallography
requires the design of recombinant constructs suitable for crystallization.
Based on the strategy used for human and mouse CRTs, we
have solved the X-ray structures of TcCRT and EhCRT. Although the
hypothesis that CRT can exhibit both open and closed conformations
has been proposed in relation to its chaperone function, only
the open conformation has yet been observed in crystal structures.
We provide the first evidence of a closed conformer in the case of
EhCRT, which involves a complex conformational transition. SAXS
experiments also provided additional information about the flexibility
of TcCRT in solution, thus complementing crystallographic
data on the open conformation. Finally, regarding the conserved
lectin domain structure and chaperone function, we now provide
direct evidence of its unusual hybrid recognition properties, with
several examples of dual carbohydrate and peptide binding.
Comparison of the structures of phylogenetically distant parasite
CRTs with their mammalian counterparts highlights key
features involved in their common structure and chaperone function.
In addition, these structures reveal species specific structural
features that might be harnessed to fight against the parasites without
affecting the functions of the host CRT. | es_ES |
