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© 2016 Wiley Periodicals, Inc. It has been proposed that integrins adopt a low affinity conformation under physiological conditions. Integrin can either be activated through cytoplasm or by binding of cations such as Mn2+ to the head domain. The cytoplasmic activation pathway, that is, inside-out signaling has been regarded as the physiological pathway for integrin activation. Integrin β8 is important for neuron vascular development. However, due to the highly divergent cytoplasmic domain, this integrin probably does not rely on inside-out signaling for affinity regulation. We therefore hypothesized that the β8 integrin uniquely assumes a constitutively high affinity state under physiological conditions. We discovered that β8 indeed exhibited high binding to soluble vitronectin in the presence of Ca2+ and the ligand binding could not be further enhanced by addition of Mn2+. The lower ectodomain stalk of the integrin, which is comprised by the integrin epidermal growth factor-like (I-EGF) domains and βTD domain, is critical for this high affinity conformation. In addition, we found that unlike other integrins, Mg2+ at low concentration inhibited β8 ligand binding. Mutagenesis studies indicated that β8 integrin possesses a unique cation binding site which might contribute to the ligand binding affinity. Our study showed that both the β8 lower ectodomain stalk and the head domain play an important role in its high affinity state under physiological conditions. J. Cell. Biochem. 118: 2044–2052, 2017. © 2016 Wiley Periodicals, Inc.

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Journal of Cellular Biochemistry

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