Structure-function analysis of the human JC polyomavirus establishes the LSTc pentasaccharide as a functional receptor motif.
The human JC polyomavirus (JCV) causes a fatal demyelinating disease, progressive multifocal leukoencephalopathy (PML), in immunocompromised individuals. Current treatment options for PML are inadequate. Sialylated oligosaccharides and the serotonin receptor are known to be necessary for JCV entry, but the molecular interactions underlying JCV attachment remain unknown. Using glycan array screening and viral infectivity assays, we identify a linear sialylated pentasaccharide with the sequence NeuNAc-α2,6-Gal-β1,4-GlcNAc-β1,3-Gal-β1,4-Glc (LSTc) present on host glycoproteins and glycolipids as a specific JCV recognition motif. The crystal structure of the JCV capsid protein VP1 was solved alone and in complex with LSTc. It reveals extensive interactions with the terminal sialic acid of the LSTc motif and specific recognition of an extended conformation of LSTc. Mutations in the JCV oligosaccharide-binding sites abolish cell attachment, viral spread, and infectivity, further validating the importance of this interaction. Our findings provide a powerful platform for the development of antiviral compounds.
Interfaculty Institute for Biochemistry, University of Tübingen, D-72076 Tübingen, Germany.
Ursula
U
Neu
Melissa S
MS
Maginnis
Angelina S
AS
Palma
Luisa J
LJ
Ströh
Christian D S
CD
Nelson
Ten
T
Feizi
Walter J
WJ
Atwood
Thilo
T
Stehle
D020816:Amino Acid Motifs; D036022:Capsid Proteins / Q000737:chemistry; D002460:Cell Line; D006023:Glycoproteins / Q000737:chemistry; D006801:Humans; D007577:JC Virus / Q000235:genetics / Q000378:metabolism*; D008968:Molecular Conformation; D019158:N-Acetylneuraminic Acid / Q000378:metabolism; D009844:Oligosaccharides / Q000737:chemistry*; D040081:Protein Array Analysis; D017434:Protein Structure, Tertiary; D011991:Receptors, Virus / Q000737:chemistry*; D012795:Sialoglycoproteins / Q000737:chemistry; D013329:Structure-Activity Relationship; D053585:Virus Attachment
D036022:Capsid Proteins; D006023:Glycoproteins; D009844:Oligosaccharides; D011991:Receptors, Virus; D012795:Sialoglycoproteins; C062481:VP1 protein, polyomavirus; D019158:N-Acetylneuraminic Acid