title: Structural and Molecular Evidence Suggesting Coronavirus-driven Evolution of Mouse Receptor.
abstract: Hosts and pathogens are locked in an evolutionary arms race. To infect mice, mouse hepatitis coronavirus (MHV) has evolved to recognize mouse CEACAM1a (mCEACAM1a) as its receptor. To elude MHV infections, mice may have evolved a variant allele from theCeacam1agene, calledCeacam1b, producing mCEACAM1b, which is a much poorer MHV receptor than mCEACAM1a. Previous studies showed that sequence differences between mCEACAM1a and mCEACAM1b in a critical MHV-binding CC' loop partially account for the low receptor activity of mCEACAM1b, but detailed structural and molecular mechanisms for the differential MHV receptor activities of mCEACAM1a and mCEACAM1b remained elusive. Here we have determined the crystal structure of mCEACAM1b and identified the structural differences and additional residue differences between mCEACAM1a and mCEACAM1b that affect MHV binding and entry. These differences include conformational alterations of the CC' loop as well as residue variations in other MHV-binding regions, including β-strands C' and C'' and loop C'C''. Using pseudovirus entry and protein-protein binding assays, we show that substituting the structural and residue features from mCEACAM1b into mCEACAM1a reduced the viral receptor activity of mCEACAM1a, whereas substituting the reverse changes from mCEACAM1a into mCEACAM1b increased the viral receptor activity of mCEACAM1b. These results elucidate the detailed molecular mechanism for how mice may have kept pace in the evolutionary arms race with MHV by undergoing structural and residue changes in the MHV receptor, providing insight into this possible example of pathogen-driven evolution of a host receptor protein.
authors.affiliation: From the Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota 55455.|the State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China.
authors.forename: Guiqing
authors.initials: G
authors.lastname: Peng
authors.affiliation: From the Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota 55455.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: From the Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota 55455.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Pasquarella
authors.affiliation: From the Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota 55455.|the Key Laboratory of Horticultural Plant Biology, Huazhong Agricultural University, Wuhan 430070, China.
authors.forename: Liqing
authors.initials: L
authors.lastname: Xu
authors.affiliation: the MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China, and.|the Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado 80045.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Qian
authors.affiliation: the Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado 80045.
authors.forename: Kathryn V
authors.initials: KV
authors.lastname: Holmes
authors.affiliation: From the Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota 55455, lifang@umn.edu.
authors.forename: Fang
authors.initials: F
authors.lastname: Li
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002272:Carcinoembryonic Antigen / Q000737:chemistry / Q000378:metabolism*; D018360:Crystallography, X-Ray; D008561:Membrane Fusion; D051379:Mice; D006517:Murine hepatitis virus / Q000378:metabolism* / Q000502:physiology; D009154:Mutation; D011487:Protein Conformation; D011991:Receptors, Virus / Q000737:chemistry / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
chemical_list: D002272:Carcinoembryonic Antigen; C486183:Ceacam1 protein, mouse; D011991:Receptors, Virus
keywords: X-ray crystallography; evolution; receptor structure-function; virus; virus entry