1KCQ

Human Gelsolin Domain 2 with a Cd2+ bound

Summary for 1KCQ

• Entry DOI: 10.2210/pdb1kcq/pdb
• Descriptor: GELSOLIN, CADMIUM ION (3 entities in total)
• Functional Keywords: alpha-beta structure, actin-binding protein, familial amyloidosis--finnish type, cadmium binding, metal binding, structural protein
• Biological source: Homo sapiens (human)
• Cellular location: Isoform 2: Cytoplasm, cytoskeleton. Isoform 1: Secreted: P06396
• Total number of polymer chains: 1
• Total formula weight: 12042.61

Authors

Kazmirski, S.L.,Isaacson, R.L.,An, C.,Buckle, A.,Johnson, C.M.,Daggett, V.,Fersht, A.R. (deposition date: 2001-11-09, release date: 2002-01-04, Last modification date: 2023-08-16)

Primary citation

Kazmirski, S.L.,Isaacson, R.L.,An, C.,Buckle, A.,Johnson, C.M.,Daggett, V.,Fersht, A.R.
Loss of a metal-binding site in gelsolin leads to familial amyloidosis-Finnish type.
Nat.Struct.Biol., 9:112-116, 2002

PubMed Abstract: 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.

PubMed: 11753432
DOI: 10.1038/nsb745

Experimental method

X-RAY DIFFRACTION (1.65 Å)