The Relationship between APOL1 Structure and Function: Clinical Implications

Madhavan, Sethu M.; Buck, Matthias

doi:10.34067/kid.0002482020

Cited by 5 publications

(3 citation statements)

References 71 publications

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“…Our study of the APOL1 C-terminal region structure complements and advances our understanding of APOL1 structure and function (6,26,27,30), further appreciating the results from computational modeling, by reference to experimental information. We also further advance the hypothesis that subtle structural, if not protein dynamics/stability changes induced by APOL1 kidney disease-associated variants could drive intracellular mechanisms in podocytes that predispose to the pathogenesis of kidney disease (22). The C-terminal domain of reference and variant APOL1 could undergo differential structural changes in response to a “second stress” stimuli attenuating the ability of the G1 and G2 variants to initiate and maintain the protein networks necessary to maintain normal podocyte homeostasis.…”

Section: Discussionmentioning

confidence: 60%

“…These studies have shown that APOL1 variants dysregulate cellular homeostasis resulting in increased lysosomal permeability, loss of mitochondrial membrane integrity and cellular energy depletion, endoplasmic reticulum stress, and disordered vesicular trafficking (6,10–21). In principle, these studies suggest that a change in the protein structure-function relationship could be responsible for the increased CKD risk of the two APOL1 variants, G1 and G2 (22). The biological function of proteins is usually intricately linked to their three-dimensional structure and, in many cases, also their stability, if not specific dynamic fluctuations in the protein.…”

Section: Introductionmentioning

confidence: 99%

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Towards the NMR solution Structure and the Dynamics of the C-terminal Region of APOL1 and its G1, G2 Variants with a Membrane Mimetic

Madhavan

Hansen

Cao

et al. 2021

Preprint

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Secreted apolipoprotein L1 (APOL1) is well known as an innate immune factor, protecting against African trypanosomiasis. The intracellular form has multiple functions, including regulating autophagy, intracellular vesicle trafficking, and ion channel activity. The APOL1 protein (G0) has two common variants (denoted G1 and G2) in the C-terminal region and are associated with a high risk of chronic kidney disease (CKD) and progression to end-stage kidney disease. Our previous studies using molecular modeling suggested that APOL1 G1 and G2 stabilize an autoinhibited state of the C-terminus, leading to impaired intracellular interactions with SNARE proteins. To characterize the structural consequence of kidney disease-associated APOL1 variants further, we assigned the C-terminal region proteins using 1H, 13C, 15N multidimensional nuclear magnetic resonance (NMR) spectra in solution in the presence of membrane mimetic dodecylphosphocholine micelles. We then derived models for the three-dimensional structure of APOL1-G0, and -G1 and -G2 variant C-terminal regions using the chemical shifts of the main chain nuclei followed by NMR relaxation measurements. The data suggest that changes in the three-dimensional structure of APOL1 C-terminal region induced by kidney disease-associated variants, not least the alteration of key sidechains and their interactions, could disrupt membrane association and the yet to be characterized protein-protein interactions including its binding partners, such as SNARE proteins. Such interactions could underlie the intracellular mechanisms that mediate the pathogenesis of CKD. In the future, one may try to reverse such structural and dynamics changes in the protein by designing agents that may bind and then mitigate APOL1 variant-associated CKD.

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Section: Discussionmentioning

confidence: 60%

Section: Introductionmentioning

confidence: 99%

Towards the NMR solution Structure and the Dynamics of the C-terminal Region of APOL1 and its G1, G2 Variants with a Membrane Mimetic

Madhavan

Hansen

Cao

et al. 2021

Preprint

Self Cite

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“…An NMR study of the SRA-ID demonstrated that it is well-structured in solution 58 and structural models predicted a coiled coil conformation 17 , 49 , 58 . However, the studies are at variance with respect to the structural influences of the disease-causing mutations G1 and G2, which were found to either stabilize 49 or destabilize 58 this conformation, perhaps due to the different lengths of SRA-ID constructs used by these groups 60 . Notwithstanding, the coiled coil model seems in conflict with the recently proposed cation channel model in which the transmembrane pore-lining region (L335–S356) 43 , roughly corresponding to the N-terminal helix of the coiled coil model, would be sequestered within the membrane and, thus, unable to participate in a coiled coil structure.…”

Section: Introductionmentioning

confidence: 99%

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

Ultsch¹,

Holliday²,

Gerhardy³

et al. 2021

Commun Biol

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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.

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Cholesterol transport and beyond: Illuminating the versatile functions of HDL apolipoproteins through structural insights and functional implications

Bhale,

Meilhac,

d'Hellencourt

et al. 2024

BioFactors

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High‐density lipoproteins (HDLs) play a vital role in lipid metabolism and cardiovascular health, as they are intricately involved in cholesterol transport and inflammation modulation. The proteome of HDL particles is indeed complex and distinct from other components in the bloodstream. Proteomics studies have identified nearly 285 different proteins associated with HDL; however, this review focuses more on the 15 or so traditionally named “apo” lipoproteins. Important lipid metabolizing enzymes closely working with the apolipoproteins are also discussed. Apolipoproteins stand out for their integral role in HDL stability, structure, function, and metabolism. The unique structure and functions of each apolipoprotein influence important processes such as inflammation regulation and lipid metabolism. These interactions also shape the stability and performance of HDL particles. HDLs apolipoproteins have multifaceted roles beyond cardiovascular diseases (CVDs) and are involved in various physiological processes and disease states. Therefore, a detailed exploration of these apolipoproteins can offer valuable insights into potential diagnostic markers and therapeutic targets. This comprehensive review article aims to provide an in‐depth understanding of HDL apolipoproteins, highlighting their distinct structures, functions, and contributions to various physiological processes. Exploiting this knowledge holds great potential for improving HDL function, enhancing cholesterol efflux, and modulating inflammatory processes, ultimately benefiting individuals by limiting the risks associated with CVDs and other inflammation‐based pathologies. Understanding the nature of all 15 apolipoproteins expands our knowledge of HDL metabolism, sheds light on their pathological implications, and paves the way for advancements in the diagnosis, prevention, and treatment of lipid and inflammatory‐related disorders.

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The Relationship between APOL1 Structure and Function: Clinical Implications

Abstract: This is an Early Access article. Please select the PDF button, above, to view it.

Cited by 5 publications

References 71 publications

Towards the NMR solution Structure and the Dynamics of the C-terminal Region of APOL1 and its G1, G2 Variants with a Membrane Mimetic

Towards the NMR solution Structure and the Dynamics of the C-terminal Region of APOL1 and its G1, G2 Variants with a Membrane Mimetic

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

Cholesterol transport and beyond: Illuminating the versatile functions of HDL apolipoproteins through structural insights and functional implications

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