View source for 6jeg


==Crystal structure of calcium free human gelsolin amyloid mutant G167R==
<StructureSection load='6jeg' size='340' side='right'caption='[[6jeg]], [[Resolution|resolution]] 2.98&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6jeg]] is a 2 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=6JEG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6JEG FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.975&#8491;</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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6jeg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6jeg OCA], [https://pdbe.org/6jeg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6jeg RCSB], [https://www.ebi.ac.uk/pdbsum/6jeg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6jeg ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/GELS_HUMAN GELS_HUMAN] Defects in GSN are the cause of amyloidosis type 5 (AMYL5) [MIM:[https://omim.org/entry/105120 105120]; also known as familial amyloidosis Finnish type. AMYL5 is a hereditary generalized amyloidosis due to gelsolin amyloid deposition. It is typically characterized by cranial neuropathy and lattice corneal dystrophy. Most patients have modest involvement of internal organs, but severe systemic disease can develop in some individuals causing peripheral polyneuropathy, amyloid cardiomyopathy, and nephrotic syndrome leading to renal failure.<ref>PMID:2157434</ref> <ref>PMID:2153578</ref> <ref>PMID:2176481</ref> <ref>PMID:1338910</ref> 
== Function ==
[https://www.uniprot.org/uniprot/GELS_HUMAN GELS_HUMAN] Calcium-regulated, actin-modulating protein that binds to the plus (or barbed) ends of actin monomers or filaments, preventing monomer exchange (end-blocking or capping). It can promote the assembly of monomers into filaments (nucleation) as well as sever filaments already formed. Plays a role in ciliogenesis.<ref>PMID:20393563</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
In the disease familial amyloidosis, Finnish type (FAF), also known as AGel amyloidosis (AGel), the mechanism by which point mutations in the calcium-regulated actin-severing protein gelsolin lead to furin cleavage is not understood in the intact protein. Here, we provide a structural and biochemical characterization of the FAF variants. X-ray crystallography structures of the FAF mutant gelsolins demonstrate that the mutations do not significantly disrupt the calcium-free conformations of gelsolin. Small-angle X-ray-scattering (SAXS) studies indicate that the FAF calcium-binding site mutants are slower to activate, whereas G167R is as efficient as the wild type. Actin-regulating studies of the gelsolins at the furin cleavage pH (6.5) show that the mutant gelsolins are functional, suggesting that they also adopt relatively normal active conformations. Deletion of gelsolin domains leads to sensitization to furin cleavage, and nanobody-binding protects against furin cleavage. These data indicate instability in the second domain of gelsolin (G2), since loss or gain of G2-stabilizing interactions impacts the efficiency of cleavage by furin. To demonstrate this principle, we engineered non-FAF mutations in G3 that disrupt the G2-G3 interface in the calcium-activated structure. These mutants led to increased furin cleavage. We carried out molecular dynamics (MD) simulations on the FAF and non-FAF mutant G2-G3 fragments of gelsolin. All mutants showed an increase in the distance between the center of masses of the 2 domains (G2 and G3). Since G3 covers the furin cleavage site on G2 in calcium-activated gelsolin, this suggests that destabilization of this interface is a critical step in cleavage.

The role of gelsolin domain 3 in familial amyloidosis (Finnish type).,Zorgati H, Larsson M, Ren W, Sim AYL, Gettemans J, Grimes JM, Li W, Robinson RC Proc Natl Acad Sci U S A. 2019 Jul 9;116(28):13958-13963. doi:, 10.1073/pnas.1902189116. Epub 2019 Jun 26. PMID:31243148<ref>PMID:31243148</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6jeg" style="background-color:#fffaf0;"></div>

==See Also==
*[[Gelsolin 3D structures|Gelsolin 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Robinson RC]]
[[Category: Zorgati H]]