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| | <StructureSection load='6oa6' size='340' side='right'caption='[[6oa6]], [[Resolution|resolution]] 1.37Å' scene=''> | | <StructureSection load='6oa6' size='340' side='right'caption='[[6oa6]], [[Resolution|resolution]] 1.37Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6oa6]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6OA6 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6OA6 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6oa6]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6OA6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6OA6 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.37Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6o31|6o31]], [[2r0o|2r0o]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ACTN4 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6oa6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6oa6 OCA], [https://pdbe.org/6oa6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6oa6 RCSB], [https://www.ebi.ac.uk/pdbsum/6oa6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6oa6 ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6oa6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6oa6 OCA], [http://pdbe.org/6oa6 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6oa6 RCSB], [http://www.ebi.ac.uk/pdbsum/6oa6 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6oa6 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/ACTN4_HUMAN ACTN4_HUMAN]] Defects in ACTN4 are the cause of focal segmental glomerulosclerosis type 1 (FSGS1) [MIM:[http://omim.org/entry/603278 603278]]. A renal pathology defined by the presence of segmental sclerosis in glomeruli and resulting in proteinuria, reduced glomerular filtration rate and edema. Renal insufficiency often progresses to end-stage renal disease, a highly morbid state requiring either dialysis therapy or kidney transplantation.<ref>PMID:10700177</ref> | + | [https://www.uniprot.org/uniprot/ACTN4_HUMAN ACTN4_HUMAN] Defects in ACTN4 are the cause of focal segmental glomerulosclerosis type 1 (FSGS1) [MIM:[https://omim.org/entry/603278 603278]. A renal pathology defined by the presence of segmental sclerosis in glomeruli and resulting in proteinuria, reduced glomerular filtration rate and edema. Renal insufficiency often progresses to end-stage renal disease, a highly morbid state requiring either dialysis therapy or kidney transplantation.<ref>PMID:10700177</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/ACTN4_HUMAN ACTN4_HUMAN]] F-actin cross-linking protein which is thought to anchor actin to a variety of intracellular structures. This is a bundling protein. Probably involved in vesicular trafficking via its association with the CART complex. The CART complex is necessary for efficient transferrin receptor recycling but not for EGFR degradation. | + | [https://www.uniprot.org/uniprot/ACTN4_HUMAN ACTN4_HUMAN] F-actin cross-linking protein which is thought to anchor actin to a variety of intracellular structures. This is a bundling protein. Probably involved in vesicular trafficking via its association with the CART complex. The CART complex is necessary for efficient transferrin receptor recycling but not for EGFR degradation. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 6oa6" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6oa6" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Actinin 3D structures|Actinin 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Birrane, G]] | + | [[Category: Birrane G]] |
| - | [[Category: Feng, D]] | + | [[Category: Feng D]] |
| - | [[Category: Actin- binding protein]]
| + | |
| - | [[Category: Actin-crosslinking]]
| + | |
| - | [[Category: Calponin homology domain]]
| + | |
| - | [[Category: Ch domain]]
| + | |
| - | [[Category: Disease mutation]]
| + | |
| - | [[Category: Glomeruloscleros spectrin family]]
| + | |
| - | [[Category: Nucleus]]
| + | |
| - | [[Category: Phosphorylation]]
| + | |
| - | [[Category: Structural protein]]
| + | |
| Structural highlights
Disease
ACTN4_HUMAN Defects in ACTN4 are the cause of focal segmental glomerulosclerosis type 1 (FSGS1) [MIM:603278. A renal pathology defined by the presence of segmental sclerosis in glomeruli and resulting in proteinuria, reduced glomerular filtration rate and edema. Renal insufficiency often progresses to end-stage renal disease, a highly morbid state requiring either dialysis therapy or kidney transplantation.[1]
Function
ACTN4_HUMAN F-actin cross-linking protein which is thought to anchor actin to a variety of intracellular structures. This is a bundling protein. Probably involved in vesicular trafficking via its association with the CART complex. The CART complex is necessary for efficient transferrin receptor recycling but not for EGFR degradation.
Publication Abstract from PubMed
BACKGROUND: Genetic mutations in alpha-actinin-4 (ACTN4)-an important actin crosslinking cytoskeletal protein that provides structural support for kidney podocytes-have been linked to proteinuric glomerulosclerosis in humans. However, the effect of post-translational modifications of ACTN4 on podocyte integrity and kidney function is not known. METHODS: Using mass spectrometry, we found that ACTN4 is phosphorylated at serine (S) 159 in human podocytes. We used phosphomimetic and nonphosphorylatable ACTN4 to comprehensively study the effects of this phosphorylation in vitro and in vivo. We conducted x-ray crystallography, F-actin binding and bundling assays, and immunofluorescence staining to evaluate F-actin alignment. Microfluidic organ-on-a-chip technology was used to assess for detachment of podocytes simultaneously exposed to fluid flow and cyclic strain. We then used CRISPR/Cas9 to generate mouse models and assessed for renal injury by measuring albuminuria and examining kidney histology. We also performed targeted mass spectrometry to determine whether high extracellular glucose or TGF-beta levels increase phosphorylation of ACTN4. RESULTS: Compared with the wild type ACTN4, phosphomimetic ACTN4 demonstrated increased binding and bundling activity with F-actin in vitro. Phosphomimetic Actn4 mouse podocytes exhibited more spatially correlated F-actin alignment and a higher rate of detachment under mechanical stress. Phosphomimetic Actn4 mice developed proteinuria and glomerulosclerosis after subtotal nephrectomy. Moreover, we found that exposure to high extracellular glucose or TGF-beta stimulates phosphorylation of ACTN4 at S159 in podocytes. CONCLUSIONS: These findings suggest that increased phosphorylation of ACTN4 at S159 leads to biochemical, cellular, and renal pathology that is similar to pathology resulting from human disease-causing mutations in ACTN4. ACTN4 may mediate podocyte injury as a consequence of both genetic mutations and signaling events that modulate phosphorylation.
Phosphorylation of ACTN4 Leads to Podocyte Vulnerability and Proteinuric Glomerulosclerosis.,Feng D, Kumar M, Muntel J, Gurley SB, Birrane G, Stillman IE, Ding L, Wang M, Ahmed S, Schlondorff J, Alper SL, Ferrante T, Marquez SL, Ng CF, Novak R, Ingber DE, Steen H, Pollak MR J Am Soc Nephrol. 2020 Jul;31(7):1479-1495. doi: 10.1681/ASN.2019101032. Epub, 2020 Jun 15. PMID:32540856[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Kaplan JM, Kim SH, North KN, Rennke H, Correia LA, Tong HQ, Mathis BJ, Rodriguez-Perez JC, Allen PG, Beggs AH, Pollak MR. Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis. Nat Genet. 2000 Mar;24(3):251-6. PMID:10700177 doi:10.1038/73456
- ↑ Feng D, Kumar M, Muntel J, Gurley SB, Birrane G, Stillman IE, Ding L, Wang M, Ahmed S, Schlondorff J, Alper SL, Ferrante T, Marquez SL, Ng CF, Novak R, Ingber DE, Steen H, Pollak MR. Phosphorylation of ACTN4 Leads to Podocyte Vulnerability and Proteinuric Glomerulosclerosis. J Am Soc Nephrol. 2020 Jul;31(7):1479-1495. doi: 10.1681/ASN.2019101032. Epub, 2020 Jun 15. PMID:32540856 doi:http://dx.doi.org/10.1681/ASN.2019101032
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