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3ffn
From Proteopedia
| 3ffn, resolution 3.00Å () | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Gene: | GSN (Homo sapiens) | ||||||||
| Related: | 1d0n, 1h1v, 1p8x, 1p8z, 1rgi, 2fgh | ||||||||
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| Resources: | FirstGlance, OCA, RCSB, PDBsum | ||||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||||
Contents |
Crystal structure of calcium-free human gelsolin
Gelsolin consists of six homologous domains (G1-G6), each containing a conserved Ca-binding site. Occupation of a subset of these sites enables gelsolin to sever and cap actin filaments in a Ca-dependent manner. Here, we present the structures of Ca-free human gelsolin and of Ca-bound human G1-G3 in a complex with actin. These structures closely resemble those determined previously for equine gelsolin. However, the G2 Ca-binding site is occupied in the human G1-G3/actin structure, whereas it is vacant in the equine version. In-depth comparison of the Ca-free and Ca-activated, actin-bound human gelsolin structures suggests G2 and G6 to be cooperative in binding Ca(2+) and responsible for opening the G2-G6 latch to expose the F-actin-binding site on G2. Mutational analysis of the G2 and G6 Ca-binding sites demonstrates their interdependence in maintaining the compact structure in the absence of calcium. Examination of Ca binding by G2 in human G1-G3/actin reveals that the Ca(2+) locks the G2-G3 interface. Thermal denaturation studies of G2-G3 indicate that Ca binding stabilizes this fragment, driving it into the active conformation. The G2 Ca-binding site is mutated in gelsolin from familial amyloidosis (Finnish-type) patients. This disease initially proceeds through protease cleavage of G2, ultimately to produce a fragment that forms amyloid fibrils. The data presented here support a mechanism whereby the loss of Ca binding by G2 prolongs the lifetime of partially activated, intermediate conformations in which the protease cleavage site is exposed.
Ca2+ binding by domain 2 plays a critical role in the activation and stabilization of gelsolin., Nag S, Ma Q, Wang H, Chumnarnsilpa S, Lee WL, Larsson M, Kannan B, Hernandez-Valladares M, Burtnick LD, Robinson RC, Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):13713-8. Epub 2009 Aug 4. PMID:19666512
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
About this Structure
3ffn is a 2 chain structure of Gelsolin with sequence from Homo sapiens. Full crystallographic information is available from OCA.
See Also
Reference
- Nag S, Ma Q, Wang H, Chumnarnsilpa S, Lee WL, Larsson M, Kannan B, Hernandez-Valladares M, Burtnick LD, Robinson RC. Ca2+ binding by domain 2 plays a critical role in the activation and stabilization of gelsolin. Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):13713-8. Epub 2009 Aug 4. PMID:19666512
