1kcq
From Proteopedia
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==Overview== | ==Overview== | ||
| - | Mutations in domain 2 (D2, residues 151-266) of the actin-binding protein | + | 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. |
==Disease== | ==Disease== | ||
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[[Category: Buckle, A.]] | [[Category: Buckle, A.]] | ||
[[Category: Daggett, V.]] | [[Category: Daggett, V.]] | ||
| - | [[Category: Fersht, A | + | [[Category: Fersht, A R.]] |
| - | [[Category: Isaacson, R | + | [[Category: Isaacson, R L.]] |
| - | [[Category: Johnson, C | + | [[Category: Johnson, C M.]] |
| - | [[Category: Kazmirski, S | + | [[Category: Kazmirski, S L.]] |
[[Category: CD]] | [[Category: CD]] | ||
[[Category: actin-binding protein]] | [[Category: actin-binding protein]] | ||
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[[Category: metal binding]] | [[Category: metal binding]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:32:36 2008'' |
Revision as of 11:32, 21 February 2008
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Human Gelsolin Domain 2 with a Cd2+ bound
Contents |
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.
Disease
Known disease associated with this structure: Amyloidosis, Finnish type OMIM:[137350]
About this Structure
1KCQ is a Single protein structure of sequence from Homo sapiens with as ligand. 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 Thu Feb 21 13:32:36 2008
