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Title: Structures of the ApoL1 and ApoL2 N-terminal domains reveal a non-classical four-helix bundle motif

Abstract

Apolipoprotein L1 (ApoL1) is a circulating innate immunity protein protecting against trypanosome infection. However, two ApoL1 coding variants are associated with a highly increased risk of chronic kidney disease. Here we present X-ray and NMR structures of the N-terminal domain (NTD) of ApoL1 and of its closest relative ApoL2. In both proteins, four of the five NTD helices form a four-helix core structure which is different from the classical four-helix bundle and from the pore-forming domain of colicin A. The reactivity with a conformation-specific antibody and structural models predict that this four-helix motif is also present in the NTDs of ApoL3 and ApoL4, suggesting related functions within the small ApoL family. The long helix 5 of ApoL1 is conformationally flexible and contains the BH3-like region. This BH3-like α-helix resembles true BH3 domains only in sequence and structure but not in function, since it does not bind to the pro-survival members of the Bcl-2 family, suggesting a Bcl-2-independent role in cytotoxicity. These findings should expedite a more comprehensive structural and functional understanding of the ApoL immune protein family.

Authors:
 [1]; ORCiD logo [2];  [2]; ORCiD logo [2]; ORCiD logo [3]; ORCiD logo [3]; ORCiD logo [3]; ORCiD logo [4]; ORCiD logo [2]; ORCiD logo [1]; ORCiD logo [2]
  1. Genentech Inc., South San Francisco, CA (United States). Dept. of Structural Biology
  2. Genentech Inc., South San Francisco, CA (United States). Dept. of Early Discovery Biochemistry
  3. Genentech Inc., South San Francisco, CA (United States). Dept. of Immunology
  4. Genentech Inc., South San Francisco, CA (United States). Dept. of Antibody Engineering
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
OSTI Identifier:
1812048
Grant/Contract Number:  
AC02-06CH11357; AC02-05CH11231
Resource Type:
Accepted Manuscript
Journal Name:
Communications Biology
Additional Journal Information:
Journal Volume: 4; Journal Issue: 1; Journal ID: ISSN 2399-3642
Publisher:
Springer Nature
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; X-ray crystallography; lipoproteins

Citation Formats

Ultsch, Mark, Holliday, Michael J., Gerhardy, Stefan, Moran, Paul, Scales, Suzie J., Gupta, Nidhi, Oltrabella, Francesca, Chiu, Cecilia, Fairbrother, Wayne, Eigenbrot, Charles, and Kirchhofer, Daniel. Structures of the ApoL1 and ApoL2 N-terminal domains reveal a non-classical four-helix bundle motif. United States: N. p., 2021. Web. doi:10.1038/s42003-021-02387-5.
Ultsch, Mark, Holliday, Michael J., Gerhardy, Stefan, Moran, Paul, Scales, Suzie J., Gupta, Nidhi, Oltrabella, Francesca, Chiu, Cecilia, Fairbrother, Wayne, Eigenbrot, Charles, & Kirchhofer, Daniel. Structures of the ApoL1 and ApoL2 N-terminal domains reveal a non-classical four-helix bundle motif. United States. https://doi.org/10.1038/s42003-021-02387-5
Ultsch, Mark, Holliday, Michael J., Gerhardy, Stefan, Moran, Paul, Scales, Suzie J., Gupta, Nidhi, Oltrabella, Francesca, Chiu, Cecilia, Fairbrother, Wayne, Eigenbrot, Charles, and Kirchhofer, Daniel. Tue . "Structures of the ApoL1 and ApoL2 N-terminal domains reveal a non-classical four-helix bundle motif". United States. https://doi.org/10.1038/s42003-021-02387-5. https://www.osti.gov/servlets/purl/1812048.
@article{osti_1812048,
title = {Structures of the ApoL1 and ApoL2 N-terminal domains reveal a non-classical four-helix bundle motif},
author = {Ultsch, Mark and Holliday, Michael J. and Gerhardy, Stefan and Moran, Paul and Scales, Suzie J. and Gupta, Nidhi and Oltrabella, Francesca and Chiu, Cecilia and Fairbrother, Wayne and Eigenbrot, Charles and Kirchhofer, Daniel},
abstractNote = {Apolipoprotein L1 (ApoL1) is a circulating innate immunity protein protecting against trypanosome infection. However, two ApoL1 coding variants are associated with a highly increased risk of chronic kidney disease. Here we present X-ray and NMR structures of the N-terminal domain (NTD) of ApoL1 and of its closest relative ApoL2. In both proteins, four of the five NTD helices form a four-helix core structure which is different from the classical four-helix bundle and from the pore-forming domain of colicin A. The reactivity with a conformation-specific antibody and structural models predict that this four-helix motif is also present in the NTDs of ApoL3 and ApoL4, suggesting related functions within the small ApoL family. The long helix 5 of ApoL1 is conformationally flexible and contains the BH3-like region. This BH3-like α-helix resembles true BH3 domains only in sequence and structure but not in function, since it does not bind to the pro-survival members of the Bcl-2 family, suggesting a Bcl-2-independent role in cytotoxicity. These findings should expedite a more comprehensive structural and functional understanding of the ApoL immune protein family.},
doi = {10.1038/s42003-021-02387-5},
journal = {Communications Biology},
number = 1,
volume = 4,
place = {United States},
year = {2021},
month = {7}
}

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Apolipoprotein L1-Specific Antibodies Detect Endogenous APOL1 inside the Endoplasmic Reticulum and on the Plasma Membrane of Podocytes
journal, August 2020

  • Scales, Suzie J.; Gupta, Nidhi; De Mazière, Ann M.
  • Journal of the American Society of Nephrology, Vol. 31, Issue 9
  • DOI: 10.1681/ASN.2019080829

Apolipoprotein L-I Promotes Trypanosome Lysis by Forming Pores in Lysosomal Membranes
journal, July 2005


Apolipoprotein L6, a Novel Proapoptotic Bcl-2 Homology 3–Only Protein, Induces Mitochondria-Mediated Apoptosis in Cancer Cells
journal, January 2005