7p2b

From Proteopedia

(Difference between revisions)

Revision as of 13:00, 1 February 2024

Crystal structure of human gelsolin amyloid mutant A551P

Structural highlights

7p2b is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 3Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

GELS_HUMAN Defects in GSN are the cause of amyloidosis type 5 (AMYL5) [MIM: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.^[1] ^[2] ^[3] ^[4]

Function

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.^[5]

Publication Abstract from PubMed

Gelsolin comprises six homologous domains, named G1 to G6. Single point substitutions in this protein are responsible for AGel amyloidosis, a hereditary disease causing progressive corneal lattice dystrophy, cutis laxa, and polyneuropathy. Although several different amyloidogenic variants of gelsolin have been identified, only the most common mutants present in the G2 domain have been thoroughly characterized, leading to clarification of the functional mechanism. The molecular events underlying the pathological aggregation of 3 recently identified mutations, namely A551P, E553K and M517R, all localized at the interface between G4 and G5, are here explored for the first time. Structural studies point to destabilization of the interface between G4 and G5 due to three structural determinants: beta-strand breaking, steric hindrance and/or charge repulsion, all implying impairment of interdomain contacts. Such rearrangements decrease the temperature and pressure stability of gelsolin but do not alter its susceptibility to furin cleavage, the first event in the canonical aggregation pathway. These variants also have a greater tendency to aggregate in the unproteolysed forms and exhibit higher proteotoxicity in a C. elegans-based assay. Our data suggest that aggregation of G4G5 variants follows an alternative, likely proteolysis-independent, pathway.

A novel hotspot of gelsolin instability triggers an alternative mechanism of amyloid aggregation.,Bollati M, Diomede L, Giorgino T, Natale C, Fagnani E, Boniardi I, Barbiroli A, Alemani R, Beeg M, Gobbi M, Fakin A, Mastrangelo E, Milani M, Presciuttini G, Gabellieri E, Cioni P, de Rosa M Comput Struct Biotechnol J. 2021 Nov 19;19:6355-6365. doi:, 10.1016/j.csbj.2021.11.025. eCollection 2021. PMID:34938411^[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Haltia M, Prelli F, Ghiso J, Kiuru S, Somer H, Palo J, Frangione B. Amyloid protein in familial amyloidosis (Finnish type) is homologous to gelsolin, an actin-binding protein. Biochem Biophys Res Commun. 1990 Mar 30;167(3):927-32. PMID:2157434
↑ Maury CP, Alli K, Baumann M. Finnish hereditary amyloidosis. Amino acid sequence homology between the amyloid fibril protein and human plasma gelsoline. FEBS Lett. 1990 Jan 15;260(1):85-7. PMID:2153578
↑ Ghiso J, Haltia M, Prelli F, Novello J, Frangione B. Gelsolin variant (Asn-187) in familial amyloidosis, Finnish type. Biochem J. 1990 Dec 15;272(3):827-30. PMID:2176481
↑ de la Chapelle A, Tolvanen R, Boysen G, Santavy J, Bleeker-Wagemakers L, Maury CP, Kere J. Gelsolin-derived familial amyloidosis caused by asparagine or tyrosine substitution for aspartic acid at residue 187. Nat Genet. 1992 Oct;2(2):157-60. PMID:1338910 doi:http://dx.doi.org/10.1038/ng1092-157
↑ Kim J, Lee JE, Heynen-Genel S, Suyama E, Ono K, Lee K, Ideker T, Aza-Blanc P, Gleeson JG. Functional genomic screen for modulators of ciliogenesis and cilium length. Nature. 2010 Apr 15;464(7291):1048-51. doi: 10.1038/nature08895. PMID:20393563 doi:10.1038/nature08895
↑ Bollati M, Diomede L, Giorgino T, Natale C, Fagnani E, Boniardi I, Barbiroli A, Alemani R, Beeg M, Gobbi M, Fakin A, Mastrangelo E, Milani M, Presciuttini G, Gabellieri E, Cioni P, de Rosa M. A novel hotspot of gelsolin instability triggers an alternative mechanism of amyloid aggregation. Comput Struct Biotechnol J. 2021 Nov 19;19:6355-6365. PMID:34938411 doi:10.1016/j.csbj.2021.11.025

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7p2b"

Categories: Homo sapiens | Large Structures | Bollati M | De Rosa M

@@ Line 1: / Line 1: @@
 ==Crystal structure of human gelsolin amyloid mutant A551P==
-<StructureSection load='7p2b' size='340' side='right'caption='[[7p2b]]' scene=''>
+<StructureSection load='7p2b' size='340' side='right'caption='[[7p2b]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7P2B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7P2B FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7p2b]] 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=7P2B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7P2B FirstGlance]. <br>
-</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=7p2b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7p2b OCA], [https://pdbe.org/7p2b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7p2b RCSB], [https://www.ebi.ac.uk/pdbsum/7p2b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7p2b ProSAT]</span></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]] 3&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <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'>[https://proteopedia.org/fgij/fg.htm?mol=7p2b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7p2b OCA], [https://pdbe.org/7p2b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7p2b RCSB], [https://www.ebi.ac.uk/pdbsum/7p2b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7p2b 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 ==
+Gelsolin comprises six homologous domains, named G1 to G6. Single point substitutions in this protein are responsible for AGel amyloidosis, a hereditary disease causing progressive corneal lattice dystrophy, cutis laxa, and polyneuropathy. Although several different amyloidogenic variants of gelsolin have been identified, only the most common mutants present in the G2 domain have been thoroughly characterized, leading to clarification of the functional mechanism. The molecular events underlying the pathological aggregation of 3 recently identified mutations, namely A551P, E553K and M517R, all localized at the interface between G4 and G5, are here explored for the first time. Structural studies point to destabilization of the interface between G4 and G5 due to three structural determinants: beta-strand breaking, steric hindrance and/or charge repulsion, all implying impairment of interdomain contacts. Such rearrangements decrease the temperature and pressure stability of gelsolin but do not alter its susceptibility to furin cleavage, the first event in the canonical aggregation pathway. These variants also have a greater tendency to aggregate in the unproteolysed forms and exhibit higher proteotoxicity in a C. elegans-based assay. Our data suggest that aggregation of G4G5 variants follows an alternative, likely proteolysis-independent, pathway.
+A novel hotspot of gelsolin instability triggers an alternative mechanism of amyloid aggregation.,Bollati M, Diomede L, Giorgino T, Natale C, Fagnani E, Boniardi I, Barbiroli A, Alemani R, Beeg M, Gobbi M, Fakin A, Mastrangelo E, Milani M, Presciuttini G, Gabellieri E, Cioni P, de Rosa M Comput Struct Biotechnol J. 2021 Nov 19;19:6355-6365. doi:, 10.1016/j.csbj.2021.11.025. eCollection 2021. PMID:34938411<ref>PMID:34938411</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 7p2b" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Gelsolin 3D structures|Gelsolin 3D structures]]
+== References ==
+<references/>
 __TOC__
 </StructureSection>
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
 [[Category: Bollati M]]
 [[Category: De Rosa M]]

7p2b

From Proteopedia

Revision as of 13:00, 1 February 2024

Crystal structure of human gelsolin amyloid mutant A551P

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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