Structural insights into calmodulin-regulated L-selectin ectodomain shedding.
The L-selectin glycoprotein receptor mediates the initial steps of leukocyte migration into secondary lymphoid organs and sites of inflammation. Following cell activation through the engagement of G-protein-coupled receptors or immunoreceptors, the extracellular domains of L-selectin are rapidly shed, a process negatively controlled via the binding of the ubiquitous eukaryotic calcium-binding protein calmodulin to the cytoplasmic tail of L-selectin. Here we present the solution structure of calcium-calmodulin bound to a peptide encompassing the cytoplasmic tail and part of the transmembrane domain of L-selectin. The structure and accompanying biophysical study highlight the importance of both calcium and the transmembrane segment of L-selectin in the interaction between these two proteins, suggesting that by binding this region, calmodulin regulates in an "inside-out" fashion the ectodomain shedding of the receptor. Our structure provides the first molecular insight into the emerging new role for calmodulin as a transmembrane signaling partner.
Biochemistry Research Group, Department of Biological Sciences, University of Calgary, Calgary, Alberta T2N 1N4, Canada.
Jessica L
JL
Gifford
Hiroaki
H
Ishida
Hans J
HJ
Vogel
D001665:Binding Sites; D002147:Calmodulin / Q000378:metabolism / Q000502:physiology*; D019041:L-Selectin / Q000378:metabolism*; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000378:metabolism
D002147:Calmodulin; D011994:Recombinant Proteins; D019041:L-Selectin