1kcq
From Proteopedia
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'''Human Gelsolin Domain 2 with a Cd2+ bound''' | '''Human Gelsolin Domain 2 with a Cd2+ bound''' | ||
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[[Category: Johnson, C M.]] | [[Category: Johnson, C M.]] | ||
[[Category: Kazmirski, S L.]] | [[Category: Kazmirski, S L.]] | ||
| - | [[Category: | + | [[Category: Actin-binding protein]] |
| - | [[Category: | + | [[Category: Alpha-beta structure]] |
| - | [[Category: | + | [[Category: Cadmium binding]] |
| - | [[Category: | + | [[Category: Familial amyloidosis--finnish type]] |
| - | [[Category: | + | [[Category: Metal binding]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 22:34:47 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 19:34, 2 May 2008
Human Gelsolin Domain 2 with a Cd2+ bound
Overview
Mutations in domain 2 (D2, residues 151-266) of the actin-binding protein gelsolin cause familial amyloidosis-Finnish type (FAF). These mutations, D187N or D187Y, lead to abnormal proteolysis of plasma gelsolin at residues 172-173 and a second hydrolysis at residue 243, resulting in an amyloidogenic fragment. Here we present the structure of human gelsolin D2 at 1.65 A and find that Asp 187 is part of a Cd2+ metal-binding site. Two Ca2+ ions are required for a conformational transition of gelsolin to its active form. Differential scanning calorimetry (DSC) and molecular dynamics (MD) simulations suggest that the Cd2+-binding site in D2 is one of these two Ca2+-binding sites and is essential to the stability of D2. Mutation of Asp 187 to Asn disrupts Ca2+ binding in D2, leading to instabilities upon Ca2+ activation. These instabilities make the domain a target for aberrant proteolysis, thereby enacting the first step in the cascade leading to FAF.
About this Structure
1KCQ is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Loss of a metal-binding site in gelsolin leads to familial amyloidosis-Finnish type., Kazmirski SL, Isaacson RL, An C, Buckle A, Johnson CM, Daggett V, Fersht AR, Nat Struct Biol. 2002 Feb;9(2):112-6. PMID:11753432 Page seeded by OCA on Fri May 2 22:34:47 2008
