Molecular mechanism of alpha2beta1 integrin interaction with human echovirus 1.
Conformational activation increases the affinity of integrins to their ligands. On ligand binding, further changes in integrin conformation elicit cellular signalling. Unlike any of the natural ligands of alpha2beta1 integrin, human echovirus 1 (EV1) seemed to bind more avidly a 'closed' than an activated 'open' form of the alpha2I domain. Furthermore, a mutation E336A in the alpha2 subunit, which inactivated alpha2beta1 as a collagen receptor, enhanced alpha2beta1 binding to EV1. Thus, EV1 seems to recognize an inactive integrin, and not even the virus binding could trigger the conformational activation of alpha2beta1. This was supported by the fact that the integrin clustering by EV1 did not activate the p38 MAP kinase pathway, a signalling pathway that was shown to be dependent on E336-related conformational changes in alpha2beta1. Furthermore, the mutation E336A did neither prevent EV1 induced and alpha2beta1 mediated protein kinase C activation nor EV1 internalization. Thus, in its entry strategy EV1 seems to rely on the activation of signalling pathways that are dependent on alpha2beta1 clustering, but do not require the conformational regulation of the receptor.
Jokinen
Johanna
J
Department of Biochemistry and Food Chemistry, University of Turku, Turku, Finland.
White
Daniel J
DJ
Salmela
Maria
M
Huhtala
Mikko
M
Käpylä
Jarmo
J
Sipilä
Kalle
K
Puranen
J Santeri
JS
Nissinen
Liisa
L
Kankaanpää
Pasi
P
Marjomäki
Varpu
V
Hyypiä
Timo
T
Johnson
Mark S
MS
Heino
Jyrki
J
D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D029822:Enterovirus B, Human / Q000472:pathogenicity* / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D038982:Integrin alpha2beta1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011991:Receptors, Virus / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D038982:Integrin alpha2beta1; D011991:Receptors, Virus; D011994:Recombinant Proteins; D048051:p38 Mitogen-Activated Protein Kinases