title: Replacing a lectin domain residue in L-selectin enhances binding to P-selectin glycoprotein ligand-1 but not to 6-sulfo-sialyl Lewis x.
abstract: Selectin-ligand interactions (bonds) mediate leukocyte rolling on vascular surfaces. The molecular basis for differential ligand recognition by selectins is poorly understood. Here, we show that substituting one residue (A108H) in the lectin domain of L-selectin increased its force-free affinity for a glycosulfopeptide binding site (2-GSP-6) on P-selectin glycoprotein ligand-1 (PSGL-1) but not for a sulfated-glycan binding site (6-sulfo-sialyl Lewis x) on peripheral node addressin. The increased affinity of L-selectinA108H for 2-GSP-6 was due to a faster on-rate and to a slower off-rate that increased bond lifetimes in the absence of force. Rather than first prolonging (catching) and then shortening (slipping) bond lifetimes, increasing force monotonically shortened lifetimes of L-selectinA108H bonds with 2-GSP-6. When compared with microspheres bearing L-selectin, L-selectinA108H microspheres rolled more slowly and regularly on 2-GSP-6 at low flow rates. A reciprocal substitution in P-selectin (H108A) caused faster microsphere rolling on 2-GSP-6. These results distinguish molecular mechanisms for L-selectin to bind to PSGL-1 and peripheral node addressin and explain in part the shorter lifetimes of PSGL-1 bonds with L-selectin than P-selectin.
authors.affiliation: Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.
authors.forename: Arkadiusz G
authors.initials: AG
authors.lastname: Klopocki
authors.forename: Tadayuki
authors.initials: T
authors.lastname: Yago
authors.forename: Padmaja
authors.initials: P
authors.lastname: Mehta
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.forename: Tao
authors.initials: T
authors.lastname: Wu
authors.forename: Anne
authors.initials: A
authors.lastname: Leppänen
authors.forename: Nicolai V
authors.initials: NV
authors.lastname: Bovin
authors.forename: Richard D
authors.initials: RD
authors.lastname: Cummings
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhu
authors.forename: Rodger P
authors.initials: RP
authors.lastname: McEver
mesh_terms: D000595:Amino Acid Sequence; D000954:Antigens, Surface / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D019041:L-Selectin / Q000737:chemistry; D037102:Lectins / Q000737:chemistry*; D008562:Membrane Glycoproteins / Q000737:chemistry*; D008565:Membrane Proteins / Q000737:chemistry; D008863:Microspheres; D008954:Models, Biological; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009844:Oligosaccharides / Q000737:chemistry*; D019007:P-Selectin / Q000737:chemistry; D017434:Protein Structure, Tertiary; D000080506:Sialyl Lewis X Antigen; D020349:Surface Plasmon Resonance
chemical_list: D000954:Antigens, Surface; C069886:L-selectin counter-receptors; D037102:Lectins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009844:Oligosaccharides; D019007:P-Selectin; C084882:P-selectin ligand protein; D000080506:Sialyl Lewis X Antigen; D019041:L-Selectin