1XK4

Crystal structure of human calprotectin(S100A8/S100A9)

Summary for 1XK4

• Entry DOI: 10.2210/pdb1xk4/pdb
• Related: 1irj 1mr8
• Descriptor: Calgranulin A, Calgranulin B, CALCIUM ION, ... (6 entities in total)
• Functional Keywords: s100 family, heterotetramer, metal binding protein
• Biological source: Homo sapiens (human); More
• Cellular location: Secreted: P05109 P06702
• Total number of polymer chains: 12
• Total formula weight: 145018.12

Authors

Korndoerfer, I.P.,Brueckner, F.,Skerra, A. (deposition date: 2004-09-26, release date: 2005-10-18, Last modification date: 2023-10-25)

Primary citation

Korndoerfer, I.P.,Brueckner, F.,Skerra, A.
The crystal structure of the human (S100A8/S100A9)2 heterotetramer, calprotectin, illustrates how conformational changes of interacting alpha-helices can determine specific association of two EF-hand proteins
J.Mol.Biol., 370:887-898, 2007

PubMed Abstract: The EF-hand proteins S100A8 and S100A9 are important calcium signalling proteins that are involved in wound healing and provide clinically relevant markers of inflammatory processes, such as rheumatoid arthritis and inflammatory bowel disease. Both can form homodimers via distinct modes of association, probably of lesser stability in the case of S100A9, whereas in the presence of calcium S100A8 and S100A9 associate to calprotectin, the physiologically active heterooligomer. Here we describe the crystal structure of the (S100A8/S100A9)(2) heterotetramer at 1.8 A resolution. Its quaternary structure illustrates how specific heteroassociation is energetically driven by a more extensive burial of solvent accessible surface areas in both proteins, most pronounced for S100A9, thus leading to a dimer of heterodimers. A major contribution to tetramer association is made by the canonical calcium binding loops in the C-terminal halves of the two proteins. The mode of heterodimerisation in calprotectin more closely resembles the subunit association previously observed in the S100A8 homodimer and provides trans stabilisation for S100A9, which manifests itself in a significantly elongated C-terminal alpha-helix in the latter. As a consequence, two different putative zinc binding sites emerge at the S100A8/S100A9 subunit interface. One of these corresponds to a high affinity arrangement of three His residues and one Asp side-chain, which is unique to the heterotetramer. This structural feature explains the well known Zn(2+) binding activity of calprotectin, whose overexpression can cause strong dysregulation of zinc homeostasis with severe clinical symptoms.

PubMed: 17553524
DOI: 10.1016/j.jmb.2007.04.065

Experimental method

X-RAY DIFFRACTION (1.8 Å)