University of Oulu

Asthana, P., Singh, D., Pedersen, J. S., Hynönen, M. J., Sulu, R., Murthy, A. V., Laitaoja, M., Jänis, J., Riley, L. W., & Venkatesan, R. (2021). Structural insights into the substrate-binding proteins Mce1A and Mce4A from Mycobacterium tuberculosis. IUCrJ 8(5), pp. 757–774,

Structural insights into the substrate-binding proteins Mce1A and Mce4A from Mycobacterium tuberculosis

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Author: Asthana, Pooja1; Singh, Dhirendra1; Pedersen, Jan Skov2;
Organizations: 1Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
2Department of Chemistry and Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Aarhus, Denmark
3Department of Chemistry, University of Eastern Finland, Joensuu, Finland
4School of Public Health, University of California, Berkeley, California, USA
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 3 MB)
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Language: English
Published: International Union of Crystallography, 2021
Publish Date: 2021-11-02


Mycobacterium tuberculosis (Mtb), which is responsible for more than a million deaths annually, uses lipids as the source of carbon and energy for its survival in the latent phase of infection. Mtb cannot synthesize all of the lipid molecules required for its growth and pathogenicity. Therefore, it relies on transporters such as the mammalian cell entry (Mce) complexes to import lipids from the host across the cell wall. Despite their importance for the survival and pathogenicity of Mtb, information on the structural properties of these proteins is not yet available. Each of the four Mce complexes in Mtb (Mce1–4) comprises six substrate-binding proteins (SBPs; MceA–F), each of which contains four conserved domains (N-terminal transmembrane, MCE, helical and C-terminal unstructured tail domains). Here, the properties of the various domains of Mtb Mce1A and Mce4A, which are involved in the import of mycolic/fatty acids and cholesterol, respectively, are reported. In the crystal structure of the MCE domain of Mce4A (MtMce4A39–140) a domain-swapped conformation is observed, whereas solution studies, including small-angle X-ray scattering (SAXS), indicate that all Mce1A and Mce4A domains are predominantly monomeric. Further, structural comparisons show interesting differences from the bacterial homologs MlaD, PqiB and LetB, which form homohexamers when assembled as functional transporter complexes. These data, and the fact that there are six SBPs in each Mtb mce operon, suggest that the MceA–F SBPs from Mce1–4 may form heterohexamers. Also, interestingly, the purification and SAXS analysis showed that the helical domains interact with the detergent micelle, suggesting that when assembled the helical domains of MceA–F may form a hydrophobic pore for lipid transport, as observed in EcPqiB. Overall, these data highlight the unique structural properties of the Mtb Mce SBPs.

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Series: IUCrJ
ISSN: 2052-2525
ISSN-E: 2052-2525
ISSN-L: 2052-2525
Volume: 8
Issue: 5
Pages: 757 - 774
DOI: 10.1107/S2052252521006199
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
Funding: This work was supported by funding from the Jane and Aatos Erkko foundation, the Sigrid Juselius Foundation, the I4Future doctoral program (MSCA-COFUND by Horizon 2020, European Union; grant agreement No. 713606), the Academy of Finland (332967) and Biocenter Oulu. RV also acknowledges the Academy of Finland for an Academy Research Fellowship (319194).
EU Grant Number: (713606) I4FUTURE - Novel Imaging and Characterisation Methods in Bio, Medical, and Environmental Research and Technology Innovations
Academy of Finland Grant Number: 332967
Detailed Information: 332967 (Academy of Finland Funding decision)
319194 (Academy of Finland Funding decision)
Copyright information: © 2021 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.