|
|
| (2 intermediate revisions not shown.) |
| Line 1: |
Line 1: |
| | | | |
| | ==Crystal structure of the 1st SH3 domain from human CD2AP (CMS) in complex with a proline-rich peptide (aa 378-393) from human RIN3== | | ==Crystal structure of the 1st SH3 domain from human CD2AP (CMS) in complex with a proline-rich peptide (aa 378-393) from human RIN3== |
| - | <StructureSection load='4wci' size='340' side='right' caption='[[4wci]], [[Resolution|resolution]] 1.65Å' scene=''> | + | <StructureSection load='4wci' size='340' side='right'caption='[[4wci]], [[Resolution|resolution]] 1.65Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4wci]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4WCI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4WCI FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4wci]] is a 6 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=4WCI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4WCI FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 1.65Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3u23|3u23]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4wci FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wci OCA], [http://pdbe.org/4wci PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4wci RCSB], [http://www.ebi.ac.uk/pdbsum/4wci PDBsum]</span></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=4wci FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wci OCA], [https://pdbe.org/4wci PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4wci RCSB], [https://www.ebi.ac.uk/pdbsum/4wci PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4wci ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/CD2AP_HUMAN CD2AP_HUMAN]] Defects in CD2AP are the cause of susceptibility to focal segmental glomerulosclerosis type 3 (FSGS3) [MIM:[http://omim.org/entry/607832 607832]]. 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:12764198</ref> | + | [https://www.uniprot.org/uniprot/CD2AP_HUMAN CD2AP_HUMAN] Defects in CD2AP are the cause of susceptibility to focal segmental glomerulosclerosis type 3 (FSGS3) [MIM:[https://omim.org/entry/607832 607832]. 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:12764198</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CD2AP_HUMAN CD2AP_HUMAN]] Seems to act as an adapter protein between membrane proteins and the actin cytoskeleton. May play a role in receptor clustering and cytoskeletal polarity in the junction between T-cell and antigen-presenting cell. May anchor the podocyte slit diaphragm to the actin cytoskeleton in renal glomerolus. Also required for cytokinesis.<ref>PMID:15800069</ref> [[http://www.uniprot.org/uniprot/RIN3_HUMAN RIN3_HUMAN]] Ras effector protein that functions as a guanine nucleotide exchange (GEF) for RAB5B and RAB31, by exchanging bound GDP for free GTP. Required for normal RAB31 function.<ref>PMID:12972505</ref> <ref>PMID:21586568</ref> | + | [https://www.uniprot.org/uniprot/CD2AP_HUMAN CD2AP_HUMAN] Seems to act as an adapter protein between membrane proteins and the actin cytoskeleton. May play a role in receptor clustering and cytoskeletal polarity in the junction between T-cell and antigen-presenting cell. May anchor the podocyte slit diaphragm to the actin cytoskeleton in renal glomerolus. Also required for cytokinesis.<ref>PMID:15800069</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Line 21: |
Line 21: |
| | </div> | | </div> |
| | <div class="pdbe-citations 4wci" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 4wci" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[CD2-associated protein 3D structures|CD2-associated protein 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Arrowsmith, C H]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Bountra, C]] | + | [[Category: Large Structures]] |
| - | [[Category: Delft, F von]] | + | [[Category: Arrowsmith CH]] |
| - | [[Category: Edwards, A M]] | + | [[Category: Bountra C]] |
| - | [[Category: Feller, S M]] | + | [[Category: Edwards AM]] |
| - | [[Category: Janning, M]] | + | [[Category: Feller SM]] |
| - | [[Category: Kirsch, K H]] | + | [[Category: Janning M]] |
| - | [[Category: Knapp, S]] | + | [[Category: Kirsch KH]] |
| - | [[Category: Krojer, T]] | + | [[Category: Knapp S]] |
| - | [[Category: Rouka, E]] | + | [[Category: Krojer T]] |
| - | [[Category: Structural genomic]]
| + | [[Category: Rouka E]] |
| - | [[Category: Simister, P C]] | + | [[Category: Simister PC]] |
| - | [[Category: Endocytosis adaptor protein protein-peptide binary complex kidney]] | + | [[Category: Von Delft F]] |
| - | [[Category: Sgc]]
| + | |
| - | [[Category: Signaling protein]]
| + | |
| Structural highlights
Disease
CD2AP_HUMAN Defects in CD2AP are the cause of susceptibility to focal segmental glomerulosclerosis type 3 (FSGS3) [MIM:607832. 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
CD2AP_HUMAN Seems to act as an adapter protein between membrane proteins and the actin cytoskeleton. May play a role in receptor clustering and cytoskeletal polarity in the junction between T-cell and antigen-presenting cell. May anchor the podocyte slit diaphragm to the actin cytoskeleton in renal glomerolus. Also required for cytokinesis.[2]
Publication Abstract from PubMed
CD2AP is an adaptor protein involved in membrane trafficking, with essential roles in maintaining podocyte function within the kidney glomerulus. CD2AP contains three Src homology 3 (SH3) domains that mediate multiple protein-protein interactions. However, a detailed comparison of the molecular binding preferences of each SH3 remained unexplored, as well as the discovery of novel interactors. Thus, we studied the binding properties of each SH3 domain to the known interactor Casitas B-lineage lymphoma protein (c-CBL), conducted a peptide array screen based on the recognition motif PxPxPR and identified 40 known or novel candidate binding proteins, such as RIN3, a RAB5-activating guanine nucleotide exchange factor. CD2AP SH3 domains 1 and 2 generally bound with similar characteristics and specificities, whereas the SH3-3 domain bound more weakly to most peptide ligands tested yet recognized an unusually extended sequence in ALG-2-interacting protein X (ALIX). RIN3 peptide scanning arrays revealed two CD2AP binding sites, recognized by all three SH3 domains, but SH3-3 appeared non-functional in precipitation experiments. RIN3 recruited CD2AP to RAB5a-positive early endosomes via these interaction sites. Permutation arrays and isothermal titration calorimetry data showed that the preferred binding motif is Px(P/A)xPR. Two high-resolution crystal structures (1.65 and 1.11 A) of CD2AP SH3-1 and SH3-2 solved in complex with RIN3 epitopes 1 and 2, respectively, indicated that another extended motif is relevant in epitope 2. In conclusion, we have discovered novel interaction candidates for CD2AP and characterized subtle yet significant differences in the recognition preferences of its three SH3 domains for c-CBL, ALIX, and RIN3.
Differential Recognition Preferences of the Three Src Homology 3 (SH3) Domains from the Adaptor CD2-associated Protein (CD2AP) and Direct Association with Ras and Rab Interactor 3 (RIN3).,Rouka E, Simister PC, Janning M, Kumbrink J, Konstantinou T, Muniz JR, Joshi D, O'Reilly N, Volkmer R, Ritter B, Knapp S, von Delft F, Kirsch KH, Feller SM J Biol Chem. 2015 Oct 16;290(42):25275-92. doi: 10.1074/jbc.M115.637207. Epub, 2015 Aug 20. PMID:26296892[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Kim JM, Wu H, Green G, Winkler CA, Kopp JB, Miner JH, Unanue ER, Shaw AS. CD2-associated protein haploinsufficiency is linked to glomerular disease susceptibility. Science. 2003 May 23;300(5623):1298-300. PMID:12764198 doi:10.1126/science.1081068
- ↑ Monzo P, Gauthier NC, Keslair F, Loubat A, Field CM, Le Marchand-Brustel Y, Cormont M. Clues to CD2-associated protein involvement in cytokinesis. Mol Biol Cell. 2005 Jun;16(6):2891-902. Epub 2005 Mar 30. PMID:15800069 doi:E04-09-0773
- ↑ Rouka E, Simister PC, Janning M, Kumbrink J, Konstantinou T, Muniz JR, Joshi D, O'Reilly N, Volkmer R, Ritter B, Knapp S, von Delft F, Kirsch KH, Feller SM. Differential Recognition Preferences of the Three Src Homology 3 (SH3) Domains from the Adaptor CD2-associated Protein (CD2AP) and Direct Association with Ras and Rab Interactor 3 (RIN3). J Biol Chem. 2015 Oct 16;290(42):25275-92. doi: 10.1074/jbc.M115.637207. Epub, 2015 Aug 20. PMID:26296892 doi:http://dx.doi.org/10.1074/jbc.M115.637207
|
