The structure of S100A12 in a hexameric form and its proposed role in receptor signalling.
S100A12 is a member of the S100 subfamily of EF-hand calcium-binding proteins; it has been shown to be one of the ligands of the 'receptor for advanced glycation end products' (RAGE) that belongs to the immunoglobulin superfamily and is involved in diabetes, Alzheimer's disease, inflammation and tumour invasion. The structure of the dimeric form of native S100A12 from human granulocytes in the presence of calcium in space group R3 has previously been reported. Here, the structure of a second crystal form in space group P2(1) (unit-cell parameters a = 53.9, b = 100.5, c = 112.7A, beta = 94.6 degrees) solved at 2.7A resolution by molecular replacement using the R3 structure as a search model is reported. Like most S100 proteins, S100A12 is a dimer. However, in the P2(1) crystal form dimers of S100A12 are arranged in a spherical hexameric assembly with an external diameter of about 55 A stabilized by calcium ions bound between adjacent dimers. The putative target-binding sites of S100A12 are located at the outer surface of the hexamer, making it possible for the hexamer to bind several targets. It is proposed that the S100A12 hexameric assembly might interact with three extracellular domains of the receptor, bringing them together into large trimeric assemblies.
Moroz
O V
OV
Department of Chemistry, University of York, York YO10 5DD, England.
Antson
A A
AA
Dodson
E J
EJ
Burrell
H J
HJ
Grist
S J
SJ
Lloyd
R M
RM
Maitland
N J
NJ
Dodson
G G
GG
Wilson
K S
KS
Lukanidin
E
E
Bronstein
I B
IB
D001665:Binding Sites; D001704:Biopolymers / Q000737:chemistry; D015153:Blotting, Western; D002135:Calcium-Binding Proteins / Q000737:chemistry* / Q000502:physiology; D003001:Cloning, Molecular; D003460:Crystallization; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D009418:S100 Proteins; D000067616:S100A12 Protein; D015398:Signal Transduction / Q000502:physiology*
D001704:Biopolymers; D002135:Calcium-Binding Proteins; D009418:S100 Proteins; D000067616:S100A12 Protein; C090441:S100A12 protein, human