Dataset Information

PLA₂R binds to the annexin A2-S100A10 complex in human podocytes.

ABSTRACT: Phospholipase A₂ receptor (PLA₂R) is a member of the mannose receptor family found in podocytes in human kidney. PLA₂R is the target of the autoimmune disease, membranous nephropathy, characterised by production of anti-PLA₂R autoantibodies which bind to the podocyte. However the function of PLA₂R in health and in disease remains unclear. To gain insight into the molecular mechanisms of PLA₂R function, we searched for its endogenous binding partners. Proteomic analysis identified annexinA2 as a potential interactor with the extracellular domains of PLA₂R. We confirmed that PLA₂R binds to annexinA2-S100A10 (A2t) complex with specific high affinity to the S100A10 component. The binding occured within the PLA₂R NC3 fragment and was increased in acidic pH. Furthermore Ca²⁺ promoted the association of the PLA₂R-A2t complex with phospholipid membranes in vitro. Within the podocyte, all three proteins were enriched in the plasma membrane and organelle membrane compartments. PLA₂R co-localised with S100A10 at the cell surface and in extracellular vesicles. This novel interaction between PLA₂R and the A2t complex offers insights into the role of PLA₂R in podocytes and how autoantibodies might disrupt PLA₂R function. The ability of podocytes to secrete vesicles containing PLA₂R provides a route for engagement of PLA₂R with the immune system.

SUBMITTER: Fresquet M

PROVIDER: S-EPMC5537237 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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PLA2R binds to the annexin A2-S100A10 complex in human podocytes.

Fresquet Maryline M Jowitt Thomas A TA McKenzie Edward A EA Ball Matthew D MD Randles Michael J MJ Lennon Rachel R Brenchley Paul E PE

Scientific reports 20170731 1

Phospholipase A2 receptor (PLA2R) is a member of the mannose receptor family found in podocytes in human kidney. PLA2R is the target of the autoimmune disease, membranous nephropathy, characterised by production of anti-PLA2R autoantibodies which bind to the podocyte. However the function of PLA2R in health and in disease remains unclear. To gain insight into the molecular mechanisms of PLA2R function, we searched for its endogeno ...[more]

PMID: 28761153

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Project description:AHNAK, a large 629 kDa protein, has been implicated in membrane repair, and the annexin A2-S100A10 heterotetramer [(p11)(2)(AnxA2)(2))] has high affinity for several regions of its 1002-amino-acid C-terminal domain. (p11)(2)(AnxA2)(2) is often localized near the plasma membrane, and this C2-symmetric platform is proposed to be involved in the bridging of membrane vesicles and trafficking of proteins to the plasma membrane. All three proteins co-localize at the intracellular face of the plasma membrane in a Ca(2+)-dependent manner. The binding of AHNAK to (p11)(2)(AnxA2)(2) has been studied previously, and a minimal binding motif has been mapped to a 20-amino-acid peptide corresponding to residues 5654-5673 of the AHNAK C-terminal domain. Here, the 2.5 Å resolution crystal structure of this 20-amino-acid peptide of AHNAK bound to the AnxA2-S100A10 heterotetramer (1:2:2 symmetry) is presented, which confirms the asymmetric arrangement first described by Rezvanpour and coworkers and explains why the binding motif has high affinity for (p11)(2)(AnxA2)(2). Binding of AHNAK to the surface of (p11)(2)(AnxA2)(2) is governed by several hydrophobic interactions between side chains of AHNAK and pockets on S100A10. The pockets are large enough to accommodate a variety of hydrophobic side chains, allowing the consensus sequence to be more general. Additionally, the various hydrogen bonds formed between the AHNAK peptide and (p11)(2)(AnxA2)(2) most often involve backbone atoms of AHNAK; as a result, the side chains, particularly those that point away from S100A10/AnxA2 towards the solvent, are largely interchangeable. While the structure-based consensus sequence allows interactions with various stretches of the AHNAK C-terminal domain, comparison with other S100 structures reveals that the sequence has been optimized for binding to S100A10. This model adds new insight to the understanding of the specific interactions that occur in this membrane-repair scaffold.

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PLA₂R binds to the annexin A2-S100A10 complex in human podocytes.

Publications

PLA<sub>2</sub>R binds to the annexin A2-S100A10 complex in human podocytes.

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