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

Journal Article · · Communications Biology
 [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

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.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
Grant/Contract Number:
AC02-05CH11231; AC02-06CH11357
OSTI ID:
1812048
Journal Information:
Communications Biology, Journal Name: Communications Biology Journal Issue: 1 Vol. 4; ISSN 2399-3642
Publisher:
Springer NatureCopyright Statement
Country of Publication:
United States
Language:
ENGLISH

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