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APOL1 variants change C-terminal conformational dynamics and binding to SNARE protein VAMP8.

Publication ,  Journal Article
Madhavan, SM; O'Toole, JF; Konieczkowski, M; Barisoni, L; Thomas, DB; Ganesan, S; Bruggeman, LA; Buck, M; Sedor, JR
Published in: JCI Insight
July 20, 2017

APOL1 variants in African populations mediate resistance to trypanosomal infection but increase risk for kidney diseases through unknown mechanisms. APOL1 is expressed in glomerular podocytes and does not vary with underlying kidney disease diagnoses or APOL1 genotypes, suggesting that the kidney disease-associated variants dysregulate its function rather than its localization or abundance. Structural homology searches identified vesicle-associated membrane protein 8 (VAMP8) as an APOL1 protein interactor. VAMP8 colocalizes with APOL1 in the podocyte, and the APOL1:VAMP8 interaction was confirmed biochemically and with surface plasmon resonance. APOL1 variants attenuate this interaction. Computational modeling of APOL1's 3-dimensional structure, followed by molecular dynamics simulations, revealed increased motion of the C-terminal domain of reference APOL1 compared with either variant, suggesting that the variants stabilize a closed or autoinhibited state that diminishes protein interactions with VAMP8. Changes in ellipticity with increasing urea concentrations, as assessed by circular dichroism spectroscopy, showed higher conformational stability of the C-terminal helix of the variants compared with the reference protein. These results suggest that reference APOL1 interacts with VAMP8-coated vesicles, a process attenuated by variant-induced reduction in local dynamics of the C-terminal. Disordered vesicular trafficking in the podocyte may cause injury and progressive chronic kidney diseases in susceptible African Americans subjects.

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Published In

JCI Insight

DOI

EISSN

2379-3708

Publication Date

July 20, 2017

Volume

2

Issue

14

Location

United States

Related Subject Headings

  • 42 Health sciences
  • 32 Biomedical and clinical sciences
 

Citation

APA
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ICMJE
MLA
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Madhavan, S. M., O’Toole, J. F., Konieczkowski, M., Barisoni, L., Thomas, D. B., Ganesan, S., … Sedor, J. R. (2017). APOL1 variants change C-terminal conformational dynamics and binding to SNARE protein VAMP8. JCI Insight, 2(14). https://doi.org/10.1172/jci.insight.92581
Madhavan, Sethu M., John F. O’Toole, Martha Konieczkowski, Laura Barisoni, David B. Thomas, Santhi Ganesan, Leslie A. Bruggeman, Matthias Buck, and John R. Sedor. “APOL1 variants change C-terminal conformational dynamics and binding to SNARE protein VAMP8.JCI Insight 2, no. 14 (July 20, 2017). https://doi.org/10.1172/jci.insight.92581.
Madhavan SM, O’Toole JF, Konieczkowski M, Barisoni L, Thomas DB, Ganesan S, et al. APOL1 variants change C-terminal conformational dynamics and binding to SNARE protein VAMP8. JCI Insight. 2017 Jul 20;2(14).
Madhavan, Sethu M., et al. “APOL1 variants change C-terminal conformational dynamics and binding to SNARE protein VAMP8.JCI Insight, vol. 2, no. 14, July 2017. Pubmed, doi:10.1172/jci.insight.92581.
Madhavan SM, O’Toole JF, Konieczkowski M, Barisoni L, Thomas DB, Ganesan S, Bruggeman LA, Buck M, Sedor JR. APOL1 variants change C-terminal conformational dynamics and binding to SNARE protein VAMP8. JCI Insight. 2017 Jul 20;2(14).

Published In

JCI Insight

DOI

EISSN

2379-3708

Publication Date

July 20, 2017

Volume

2

Issue

14

Location

United States

Related Subject Headings

  • 42 Health sciences
  • 32 Biomedical and clinical sciences