Structural basis for non-canonical integrin engagement by Bordetella adenylate cyclase toxin

Blockade of the Adenylate Cyclase Toxin Synergizes with Opsonizing Antibodies to Protect Mice against Bordetella pertussis

“…To assess the relevance of the mouse model for human infection, we compared the sensitivities of human and mouse α M β 2 integrins to ACT binding and intoxication. The levels of binding of ACT to each purified integrin were similar: a K d of 57 nM was previously measured by surface plasmon resonance (SPR) for RTX 751 binding to human α M β 2 integrin ( 20 ), versus 52 nM for RTX 751 binding to mouse α M β 2 integrin here, with similar on- and off-rates ( k on of 7.8 × 10 4 versus 5.5 × 10 4 M −1 s −1 and k off of 4.4 × 10 −3 versus 2.8 × 10 −3 s −1 for human versus mouse integrins, respectively) ( Fig. 3B ).…”

“…Antibodies M1H5 and M2B10 neutralize ACT by sterically blocking RTX-receptor interactions, M2B10 by binding the first linker (L1) and M1H5 by binding L2 ( 19 , 26 ), while the nonneutralizing antibody M1F5 binds L3 ( Fig. 2A ) ( 20 ). Antibody M1F5 was included to evaluate the potential for anti-ACT antibodies to directly mediate antibacterial effects such as complement lysis or opsonophagocytosis by binding to B. pertussis -associated ACT.…”

“…In addition to the N-terminal catalytic domain, ACT includes an acylated hydrophobic domain, which is likely involved in the translocation of the catalytic domain, and a C-terminal repeat-in-toxin (RTX) domain. Structurally, the RTX domain is comprised of five beta roll blocks joined by linkers that mediate receptor and antibody binding ( 19 ), with antibodies binding some linkers neutralizing ACT by sterically inhibiting RTX-receptor interactions ( 20 , 21 ).…”

αMI-domain of Integrin Mac-1 Binds the Cytokine Pleiotrophin Using Multiple Mechanisms

“…Recently, it was also shown to bind SIRPα and mediate the merging of macrophages (Podolnikova et al, 2019). Although many ligands are known to bind Mac-1, the binding mechanisms of only a handful of ligands were confirmed with structures (Bajic et al, 2013;Jensen et al, 2016;Morgan et al, 2019;Trstenjak et al, 2020;Fernandez et al, 2022;Goldsmith et al, 2022). The binding interactions of other ligands and their functional consequences remain to be elucidated.…”

Family-wide analysis of integrin structures predicted by AlphaFold2

“…Since the publication of the first high-resolution crystal structure of the α V β 3 ectodomain in 2001 [10], substantial efforts have been dedicated to determining integrin structures using a variety of methods, including crystallography, negative-stain electron microscopy (EM), nuclear magnetic resonance (NMR), and more recently, cryogenic EM (cryo-EM). However, high-resolution structure information remains limited to only a few integrin members, including α V β 3 [10][11][12], [10][11][12] α IIb β 3 [13][14][15][16][17][18][19][20][21], [13][14][15][16][17][18][19][20][21] α 5 β 1 [22][23][24], [22][23][24] α 6 β 1 [25], 25 α X β 2 [26,27], α L β 2 [28], α M β 2 [29,30], α V β 6 [31][32][33], α V β 8 [34][35][36][37], and α 4 β 7 [38], many of which have only had the fragment structures determin...…”