Integrins are heterodimeric transmembrane proteins that play important roles in various biological processes. Most integrins serve as adhesion molecules and transmit bidirectional signaling across the cell membrane through global conformational changes from the bent closed to the extended open conformation. However, integrin β8 is distinctive in structure and function. Its cytoplasmic domain lacks the conserved protein‐binding sequence, which is important in transmitting inside‐out signals, suggesting that integrin β8 may have a different activation mechanism or lack such signaling. In addition, the ligand‐binding or activating metal ion Mn2+ does not induce a global conformational change in integrin β8. It may have only one conformation, that is, an extended, closed conformation, but with high affinity for ligands under physiological conditions, and is, therefore, considered an atypical integrin member. The extended structure and high ligand‐binding affinity of integrin αvβ8 make it ideal for encountering and binding ligands expressed on an opposing cell or in the extracellular matrix. In this review, we summarize the progress in integrin β8 research with a focus on its distinctive function and structure among integrin members.
Many integrins transmit signals through global conformational changes. However, it is unclear whether integrin αvβ8 adopts a similar mechanism during integrin activation and signaling on the cell surface. Here, we showed that disulfide‐bonded mutants, which prevented integrin αvβ8 lower leg dissociation, bound ligands with similar level as the wild‐type protein, suggesting that αvβ8 ligand binding did not require lower leg disassociation. We further showed that the N‐glycosylation mutant at the interface between the β I and hybrid domains did not affect ligand binding, suggesting that the αvβ8 open headpiece was not present on the cell surface. We proposed that αvβ8 integrin may adopt only one state, that is, the extended conformation with a closed headpiece. Our results showed that two lower legs retained heterodimeric interfaces, and this association might be important for stabilizing integrin in the extended conformation. Therefore, αvβ8 may not transmit bidirectional signals across the plasma membrane but instead may serve as an anchoring site with high affinity and high accessibility for extracellular ligands.
Integrins are transmembrane proteins that transmit bi-directional signals across the cell membrane through global structural rearrangement among three different conformational states: bent, extended-closed, and extended-open conformations. However, the β 8 integrin is distinctive and may adopt only one conformation, that is, extended-closed conformation, with high affinity for ligands under physiological conditions, and may not transmit bi-directional signals like other integrin members. It is unclear how different β 8 domains affect its unique conformation and signaling. We swapped different domains of integrin β 3 with those of β 8 and investigated how they affected integrin ligand binding, global conformation, and outside-in signaling. We found that the β 8 epidermal growth factor (EGF) domains increased integrin ligand binding ability and contributed to its extended conformation. By comparison, the β 8 transmembrane and cytoplasmic domains had little effect on ligand binding or global conformation. The β 8 EGF and transmembrane domains did not affect integrinmediated cell adhesion, cell spreading, focal adhesion formation, or colocalization of integrin with other proteins, but the cytoplasmic domain had a defective effect on outside-in signaling. Our results showed that different domains of β 8 play various roles on its unique conformation, ligand binding, and signaling, which are considered atypical among integrin members. K E Y W O R D S integrin α v β 8 , domains/function, structure/signaling 1 | INTRODUCTION Integrins are heterodimeric receptors on the cell surface, consisting of two noncovalently associated α and β subunit. In mammals, 18 α subunits and 8 β subunits assemble into 24 pairs of integrins. Each integrin consists of a large extracellular domain to which ligands bind, a single transmembrane (TM) domain, and, with the exception of β 4 , a small cytoplasmic domain (Hynes, 2002). The typical integrins carry out various biological functions through mediating cell rolling or cell-cell and/or cell-extracellular (ECM) adhesion, leading to intracellular signaling cascades. Integrin α V β 8 , however, is functionally distinctive and does not mediate cell rolling or adhesion (Nishimura et al., 1994). α V β 8 is almost exclusively expressed in the brain, kidney and placenta, and its expression is correlated with central nervous system (CNS) development (Chernousov & Carey, 2003). It is specialized in binding to cell-or matrix-attached latent transforming growth factor (TGF)-β, resulting in the release of active TGF-β, which is essential for TGF-β functions (Nishimura, 2009). Lack of the interaction between latent TGF-β and α V β 8 has been proposed to be the cause of embryonic or perinatal lethality with abnormal vascular
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