View source for 5fae


==N184K pathological variant of gelsolin domain 2 (trigonal form)==
<StructureSection load='5fae' size='340' side='right' caption='[[5fae]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5fae]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5FAE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5FAE FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1kcq|1kcq]]</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=5fae FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5fae OCA], [http://pdbe.org/5fae PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5fae RCSB], [http://www.ebi.ac.uk/pdbsum/5fae PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5fae ProSAT]</span></td></tr>
</table>
== Disease ==
[[http://www.uniprot.org/uniprot/GELS_HUMAN GELS_HUMAN]] Defects in GSN are the cause of amyloidosis type 5 (AMYL5) [MIM:[http://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 ==
[[http://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 ==
Mutations in gelsolin are responsible for a systemic amyloidosis first described in 1969. Until recently, the disease was associated with two substitutions of the same residue, leading to the loss of the calcium binding site. Novel interest arose in 2014 when the N184K variant of the protein was identified as the etiological agent of a novel kidney-localized amyloidosis. Here we provide a first rationale for N184K pathogenicity. We show that the mutation induces a destabilization of gelsolin second domain, without compromising its calcium binding capacity. X-ray data combined with molecular dynamics simulations demonstrates that the primary source of the destabilization is a loss of connectivity in proximity of the metal. Such rearrangement of the H-bond network does not have a major impact on the overall fold of the domain, nevertheless, it increases the flexibility of a stretch of the protein, which is consequently processed by furin protease. Overall our data suggest that the N184K variant is subjected to the same aberrant proteolytic events responsible for the formation of amyloidogenic fragments in the previously characterized mutants. At the same time our data suggest that a broader number of mutations, unrelated to the metal binding site, can lead to a pathogenic phenotype.

Molecular basis of a novel renal amyloidosis due to N184K gelsolin variant.,Boni F, Milani M, Porcari R, Barbiroli A, Ricagno S, de Rosa M Sci Rep. 2016 Sep 16;6:33463. doi: 10.1038/srep33463. PMID:27633054<ref>PMID:27633054</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5fae" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Bolognesi, M]]
[[Category: Boni, F]]
[[Category: Milani, M]]
[[Category: Ricagno, S]]
[[Category: Rosa, M de]]
[[Category: Amyloidosis]]
[[Category: Calcium]]
[[Category: Gelsolin]]
[[Category: Mutation]]
[[Category: Structural protein]]