5fae

From Proteopedia

Jump to: navigation, search

N184K pathological variant of gelsolin domain 2 (trigonal form)

Structural highlights

5fae is a 1 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 1.7Å
Ligands:CA, CL, PEG, SO4
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

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[6]

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

Loading citation details..
Citations
0 reviews cite this structure
Gelsolin pathogenic Gly167Arg mutation promotes domain-swap dimerization of the protein.
Bonì et al. (2018)
-1 more
7 other articles
No citations found

See Also

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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
  5. ↑ 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
  6. ↑ Boni F, Milani M, Porcari R, Barbiroli A, Ricagno S, de Rosa M. Molecular basis of a novel renal amyloidosis due to N184K gelsolin variant. Sci Rep. 2016 Sep 16;6:33463. doi: 10.1038/srep33463. PMID:27633054 doi:http://dx.doi.org/10.1038/srep33463

Contents


PDB ID 5fae

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://proteopedia.org/wiki/index.php/5fae"
Personal tools