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


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.






Published Version (Please cite this version)


Publication Info

Madhavan, Sethu M, John F O'Toole, Martha Konieczkowski, Laura Barisoni, David B Thomas, Santhi Ganesan, Leslie A Bruggeman, Matthias Buck, et al. (2017). APOL1 variants change C-terminal conformational dynamics and binding to SNARE protein VAMP8. JCI insight, 2(14). 10.1172/jci.insight.92581 Retrieved from https://hdl.handle.net/10161/22305.

This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.



Laura Barisoni

Professor of Pathology

David Thomas

Adjunct Professor in the Department of Pathology

Unless otherwise indicated, scholarly articles published by Duke faculty members are made available here with a CC-BY-NC (Creative Commons Attribution Non-Commercial) license, as enabled by the Duke Open Access Policy. If you wish to use the materials in ways not already permitted under CC-BY-NC, please consult the copyright owner. Other materials are made available here through the author’s grant of a non-exclusive license to make their work openly accessible.