6ljf

From Proteopedia

Crystal structure of gelsolin G3 domain (calcium condition)

Structural highlights

6ljf 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 1.5Å
Ligands:	CA, GOL
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 superfamily proteins, consisting of multiple domains (usually six), sever actin filaments and cap the barbed ends in a Ca(2+)-dependent manner. Two types of evolutionally conserved Ca(2+)-binding sites have been identified in this family; type-1 (between gelsolin and actin) and type-2 (within the gelsolin domain). Fragmin, a member in the slime mold Physarum polycephalum, consists of three domains (F1-F3) that are highly similar to the N-terminal half of mammalian gelsolin (G1-G3). Despite their similarities, the two proteins exhibit a significant difference in the Ca(2+) dependency; F1-F3 absolutely requires Ca(2+) for the filament severing whereas G1-G3 does not. In this study, we examined the strong dependency of fragmin on Ca(2+) using biochemical and structural approaches. Our co-sedimentation assay demonstrated that Ca(2+) significantly enhanced the binding of F2-F3 to actin. We determined the crystal structure of F2-F3 in the presence of Ca(2+). F2-F3 binds a total of three calcium ions; while two are located in type-2 sites within F2 or F3, the remaining one resides between the F2 long helix and the F3 short helix. The inter-domain Ca(2+)-coordination appears to stabilize F2-F3 in a closely packed configuration. Notably, the F3 long helix exhibits a bent conformation which is different from the straight G3 long helix in the presence of Ca(2+). Our results provide the first structural evidence for the existence of an unconventional Ca(2+)-binding site in the gelsolin superfamily proteins.

Novel inter-domain Ca(2+)-binding site in the gelsolin superfamily protein fragmin.,Takeda S, Fujiwara I, Sugimoto Y, Oda T, Narita A, Maeda Y J Muscle Res Cell Motil. 2019 Dec 20. pii: 10.1007/s10974-019-09571-5. doi:, 10.1007/s10974-019-09571-5. PMID:31863323^[6]

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

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Citations

reviews cite this structure

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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
↑ Takeda S, Fujiwara I, Sugimoto Y, Oda T, Narita A, Maeda Y. Novel inter-domain Ca(2+)-binding site in the gelsolin superfamily protein fragmin. J Muscle Res Cell Motil. 2019 Dec 20. pii: 10.1007/s10974-019-09571-5. doi:, 10.1007/s10974-019-09571-5. PMID:31863323 doi:http://dx.doi.org/10.1007/s10974-019-09571-5