Effects of conformational activation of integrin alpha 1I and alpha 2I domains on selective recognition of laminin and collagen subtypes.
Collagen receptor integrins alpha 1 beta 1 and alpha 2 beta 1 can selectively recognize different collagen subtypes. Here we show that their alpha I domains can discriminate between laminin isoforms as well: alpha 1I and alpha 2I recognized laminin-111, -211 and -511, whereas their binding to laminin-411 was negligible. Residue Arg-218 in alpha1 was found to be instrumental in high-avidity binding. The gain-of-function mutation E318W makes the alpha 2I domain to adopt the "open" high-affinity conformation, while the wild-type alpha 2I domain favors the "closed" low-affinity conformation. The E318W mutation markedly increased alpha 2I domain binding to the laminins (-111, -211 and -511), leading us to propose that the activation state of the alpha 2 beta 1 integrin defines its role as a laminin receptor. However, neither wild-type nor alpha 2IE318W domain could bind to laminin-411. alpha 2IE318W also bound tighter to all collagens than alpha 2I wild-type, but it showed reduced ability to discriminate between collagens I, IV and IX. The corresponding mutation, E317A, in the alpha 1I domain transformed the domain into a high-avidity binder of collagens I and IV. Thus, our results indicate that conformational activation of integrin alpha 1I and alpha 2I domains leads to high-avidity binding to otherwise disfavored collagen subtypes.
Tulla
Mira
M
Department of Biochemistry and Food Chemistry, University of Turku, Finland. mira.tulla@biotec.tu-dresden.de <mira.tulla@biotec.tu-dresden.de>
Lahti
Matti
M
Puranen
J Santeri
JS
Brandt
Anna-Maria
AM
Käpylä
Jarmo
J
Domogatskaya
Anna
A
Salminen
Tiina A
TA
Tryggvason
Karl
K
Johnson
Mark S
MS
Heino
Jyrki
J
D001120:Arginine / Q000737:chemistry; D003094:Collagen / Q000145:classification / Q000378:metabolism*; D006801:Humans; D039423:Integrin alpha1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D039421:Integrin alpha2 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D007797:Laminin / Q000378:metabolism*; D008958:Models, Molecular; D009154:Mutation; D011485:Protein Binding; D020033:Protein Isoforms / Q000378:metabolism; D017434:Protein Structure, Tertiary
D039423:Integrin alpha1; D039421:Integrin alpha2; D007797:Laminin; D020033:Protein Isoforms; C121346:laminin 1; C119013:laminin 10; C110308:laminin 8; D003094:Collagen; D001120:Arginine