Malaria
Multiple interests in structural models of DARC transmembrane proteinMultiples intérêts des modèles structuraux de la protéine transmembranaire Darc

https://doi.org/10.1016/j.tracli.2010.05.003Get rights and content

Abstract

Duffy Antigen Receptor for Chemokines (DARC) is an unusual transmembrane chemokine receptor which (i) binds the two main chemokine families and (ii) does not transduct any signal as it lacks the DRY consensus sequence. It is considered as silent chemokine receptor, a tank useful for chemiotactism. DARC had been particularly studied as a major actor of malaria infection by Plasmodium vivax. It is also implicated in multiple chemokine inflammation, inflammatory diseases, in cancer and might play a role in HIV infection and AIDS. In this review, we focus on the interest to build structural model of DARC to understand more precisely its abilities to bind its physiological ligand CXCL8 and its malaria ligand. We also present innovative development on VHHs able to bind DARC protein. We underline difficulties and limitations of such bioinformatics approaches and highlight the crucial importance of biological data to conduct these kinds of researches.

Résumé

Le Duffy antigen receptor for chemokines (DARC) est un récepteur aux chimiokines inhabituel qui (i) lie les deux grandes familles de chimiokines et (ii) du fait de l’absence du motif DRY ne transduit pas de signal. Récepteur silencieux, il est un réservoir utile pour le chimiotactisme. DARC a été particulièrement étudié comme un acteur majeur de l’infection par Plasmodium vivax. Il est également impliqué dans des maladies inflammatoires, cancers et pourrait jouer un rôle dans l’infection par le HIV. Nous présentons l’intérêt de construire un modèle structural de DARC, pour comprendre plus précisément sa capacité à lier son ligand physiologique CXCL8 et son ligand paludique. Nous présentons des développements innovants portant sur des VHHs capables de lier le DARC. Nous soulignons aussi les difficultés et les limites des approches bioinformatiques et mettons en évidence l’importance cruciale de données biologiques pour mener à bien ce type de recherches.

Section snippets

DARC

The history of human knowledge on Duffy Antigen Receptor for Chemokines (DARC) begins in 1950 with the discovery of a new blood groups system (the Duffy blood group system) named from the person who developed the first antibody against the so-called Fya antigen [1]. A second antithetic antigen Fyb [2] was shortly after discovered. In 1955, it was shown that antigens of Duffy blood group system were missing in red blood cells (named Fy(a-b-)) from a large proportion of West African ascent

The different aspects of the research

All these data clearly suggests that DARC is a particularly interesting and important protein. Various DARC mutants have been designed and expressed. Affinities with DARC natural ligand, CXCL8, and different antibodies [33], [51], [52], [53], [54], [55], [56], [57], [58] confirmed predictions made about DARC topology [59]. This transmembrane protein as bona fide GPCR has seven transmembrane segments with four extracellular loops (named Extra Cellular Domains [ECDs]) and four intracellular loops

Building structural models

Classically, a structural model can be elaborated through different strategies from homology/comparative modelling, threading ab initio or de novo approaches, depending on the sequence identity and the availability of structural homologous. Fig. 1 shows a rough description of the sequence identity needed for each of these approaches. If the sequence identity is high, homology modelling could be used. In the twilight zone, when PSIBLAST is unable to detect any interesting sequences, threading

Structural properties of DARC

To explore the flexibility of the ECD loops, we performed simulated annealing simulations [127]. Interestingly, the procedure highlights the importance of residue D263 which was never really accessible in any structural models; this residue constrains the local fold by creating a bridge with ECD3. Analysis of simulations with Protein Blocks [104], [128] showed that that some regions in ECD1 tent to be more helical and other ones to be more extended. These results correlated well with the

Modelling of camelid VHHs

DARC is implicated in numerous human diseases. Dedicated tools are demanded for analyzing DARC role and guiding therapeutic strategies. In this field, antibodies and their recombinant derivatives are of great use. The heavy chain-only antibodies found in camelids are composed of heavy chains and lack all light chains [142]. VHHs (or nanobodies), which correspond to the domain in the heavy chain-only antibody, can be derived. In this domain is located the antigen recognition region. VHHs are

Conclusions and perspectives

Hence, in this short review, we have presented the biological importance of DARC protein and its multiple implications in human diseases. We have underlined the interest to use structural models to better understand this protein. The building of a structural model for a transmembrane protein is a very difficult task. Comparison with up-to-date methods highlights the crucial value of biological data to produce pertinent structural models, our approach remaining the most efficient one. Using

Conflict of interest statement

No potential conflict of interest relevant to this article was reported.

Acknowledgements

D.S. was supported by scholarship from French Embassy in Warsaw and from the Flemish government. This work was supported by grants from the French Ministry of Research, université Paris Diderot - Paris 7, French National Institute for Blood Transfusion (INTS), French Institute for Health and Medical Research (INSERM). Project was supported by grant no. N N302 118835 from the Ministry of Science and Higher Education of Poland and in part by a Polonium Partenariat Hubert Curien grant.

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