1mr8
MIGRATION INHIBITORY FACTOR-RELATED PROTEIN 8 FROM HUMAN
Structural highlights
FunctionS10A8_HUMAN S100A8 is a calcium- and zinc-binding protein which plays a prominent role in the regulation of inflammatory processes and immune response. It can induce neutrophil chemotaxis and adhesion. Predominantly found as calprotectin (S100A8/A9) which has a wide plethora of intra- and extracellular functions. The intracellular functions include: facilitating leukocyte arachidonic acid trafficking and metabolism, modulation of the tubulin-dependent cytoskeleton during migration of phagocytes and activation of the neutrophilic NADPH-oxidase. Activates NADPH-oxidase by facilitating the enzyme complex assembly at the cell membrane, transfering arachidonic acid, an essential cofactor, to the enzyme complex and S100A8 contributes to the enzyme assembly by directly binding to NCF2/P67PHOX. The extracellular functions involve proinfammatory, antimicrobial, oxidant-scavenging and apoptosis-inducing activities. Its proinflammatory activity includes recruitment of leukocytes, promotion of cytokine and chemokine production, and regulation of leukocyte adhesion and migration. Acts as an alarmin or a danger associated molecular pattern (DAMP) molecule and stimulates innate immune cells via binding to pattern recognition receptors such as Toll-like receptor 4 (TLR4) and receptor for advanced glycation endproducts (AGER). Binding to TLR4 and AGER activates the MAP-kinase and NF-kappa-B signaling pathways resulting in the amplification of the proinflammatory cascade. Has antimicrobial activity towards bacteria and fungi and exerts its antimicrobial activity probably via chelation of Zn(2+) which is essential for microbial growth. Can induce cell death via autophagy and apoptosis and this occurs through the cross-talk of mitochondria and lysosomes via reactive oxygen species (ROS) and the process involves BNIP3. Can regulate neutrophil number and apoptosis by an anti-apoptotic effect; regulates cell survival via ITGAM/ITGB and TLR4 and a signaling mechanism involving MEK-ERK. Its role as an oxidant scavenger has a protective role in preventing exaggerated tissue damage by scavenging oxidants. Can act as a potent amplifier of inflammation in autoimmunity as well as in cancer development and tumor spread.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedThe structure of human MRP8 in the calcium-bound form was determined at 1.9 A resolution by X-ray crystallography. The structure was initially solved by MAD phasing of an ytterbium-substituted crystal and was refined against data obtained from a Ca(2+)-bound crystal. The dimeric form of MRP8 was stabilized by hydrophobic interactions between mutually wrapped helices. There were two EF-hand motifs per monomer and each EF-hand bound one Ca(2+) with a different affinity [the affinity of the C-terminal EF-hand (EF-2) for Ca(2+) was stronger than that of the N-terminal EF-hand (EF-1)]. Furthermore, replacement with Yb(3+) occurred in the C-terminal EF-hand only, suggesting a more flexible nature for EF-2 than for EF-1. This, combined with previous observations that the helix in EF-2 (helix III) undergoes a large conformational change upon calcium binding, suggests that the C-terminal EF-hand (EF-2) plays a role as a trigger for Ca(2+)-induced conformational change. The structure of human MRP8, a member of the S100 calcium-binding protein family, by MAD phasing at 1.9 A resolution.,Ishikawa K, Nakagawa A, Tanaka I, Suzuki M, Nishihira J Acta Crystallogr D Biol Crystallogr. 2000 May;56(Pt 5):559-66. PMID:10771424[12] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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