Mast cell and monocyte recruitment by S100A12 and its hinge domain.
S100A12 is expressed at sites of acute, chronic, and allergic inflammation. S100 proteins have regions of high sequence homology, but the "hinge" region between the conserved calcium binding domains is structurally and functionally divergent. Because the murine S100A8 hinge domain (mS100A8(42-55)) is a monocyte chemoattractant whereas the human sequence (hS100A8(43-56)) is inactive, we postulated that common hydrophobic amino acids within the S100A12 hinge sequence may be functional. The hinge domain, S100A12(38-53), was chemotactic for human monocytes and murine mast cells in vitro. S100A12(38-53) provoked an acute inflammatory response similar to that elicited by S100A12 in vivo and caused edema and leukocyte and mast cell recruitment. Circular dichroism studies showed that S100A12(38-53) had increased helical structure in hydrophobic environments. Mutations in S100A12(38-53) produced using an alanine scan confirmed that specific hydrophobic residues (I44A, I47A, and I53A) on the same face of the helix were critical for monocyte chemotaxis in vitro and generation of edema in vivo. In a hydrophobic environment such as the cell membrane, these critical residues would likely align on one face of an alpha-helix to facilitate receptor interaction. Interaction is unlikely to occur via the receptor for advanced glycation end products but, rather, via a G-protein-coupled mechanism.
Yan
Wei Xing
WX
Centre for Infection and Inflammation Research, University of New South Wales, Sydney, New South Wales 2052, Australia.
Armishaw
Chris
C
Goyette
Jesse
J
Yang
Zheng
Z
Cai
Hong
H
Alewood
Paul
P
Geczy
Carolyn L
CL
D000595:Amino Acid Sequence; D000596:Amino Acids / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002630:Chemotactic Factors / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects; D002942:Circular Dichroism; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008407:Mast Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009154:Mutation / Q000187:drug effects; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology; D009418:S100 Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D000067616:S100A12 Protein
D000596:Amino Acids; D002630:Chemotactic Factors; D010446:Peptide Fragments; D009418:S100 Proteins; D000067616:S100A12 Protein; C090441:S100A12 protein, human; D002118:Calcium