Transmembrane helices of integrin alpha and beta subunits have been implicated in the regulation of integrin activity. Two mutations, glycine-708 to asparagine-708 (G708N)and methionine-701 to asparagine-701, in the transmembrane helix of the beta3 subunit enabled integrin alphaIIbbeta3 to constitutively bind soluble fibrinogen. Further characterization of the G708N mutant revealed that it induced alphaIIbbeta3 clustering and constitutive phosphorylation of focal adhesion kinase. This mutation also enhanced the tendency of the transmembrane helix to form homotrimers. These results suggest that homomeric associations involving transmembrane domains provide a driving force for integrin activation. They also suggest a structural basis for the coincidence of integrin activation and clustering.
Optical detection of glucose, high drug loading capacity, and self-regulated drug delivery are simultaneously possible using a multifunctional hybrid nanogel particle under a rational design in a colloid chemistry method. Such hybrid nanogels are made of Ag nanoparticle (NP) cores covered by a copolymer gel shell of poly(4-vinylphenylboronic acid-co-2-(dimethylamino)ethyl acrylate) [p(VPBA-DMAEA)]. The introduction of the glucose sensitive p(VPBA-DMAEA) gel shell onto Ag NPs makes the polymer-bound Ag NPs responsive to glucose. While the small sized Ag cores (10 +/- 3 nm) provide fluorescence as an optical code, the responsive polymer gel shell can adapt to a surrounding medium of different glucose concentrations over a clinically relevant range (0-30 mM), convert the disruptions in homeostasis of glucose level into optical signals, and regulate release of preloaded insulin. This shows a new proof-of-concept for diabetes treatment that exploits the properties from each building block of a multifunctional nano-object. The highly versatile multifunctional hybrid nanogels could potentially be used for simultaneous optical diagnosis, self-regulated therapy, and monitoring of the response to treatment.
Homomeric and heteromeric interactions between the ␣IIb and 3 transmembrane domains are involved in the regulation of integrin ␣IIb3 function. These domains appear to interact in the inactivated state but separate upon integrin activation. Moreover, homomeric interactions may increase the level of ␣IIb3 activity by competing for the heteromeric interaction that specifies the resting state. To test this model, a series of mutants were examined that had been shown previously to either enhance or disrupt the homomeric association of the ␣IIb transmembrane domain. One mutation that enhanced the dimerization of the ␣IIb transmembrane domain indeed induced constitutive ␣IIb3 activation. However, a series of mutations that disrupted homodimerization also led to ␣IIb3 activation. These results suggest that the homo-and heterodimerization motifs overlap in the ␣IIb transmembrane domain, and that mutations that disrupt the ␣IIb͞3 transmembrane domain heterodimer are sufficient to activate the integrin. The data also imply a mechanism for ␣IIb3 regulation in which the integrin can be shifted from its inactive to its active state by destabilizing an ␣IIb͞3 transmembrane domain heterodimer and by stabilizing the resulting ␣IIb and 3 transmembrane domain homodimers.␣IIb3 ͉ integrin regulation ͉ transmembrane domains I ntegrins reside on cell surfaces in an equilibrium between inactive and active conformations that can be shifted in either direction by altering the distance between the stalks that anchor integrins in cell membranes (1). At the cellular level, integrin activation is regulated by cellular agonists, but how this occurs is uncertain. In the case of the platelet integrin ␣IIb3, membrane-proximal segments of the ␣IIb and 3 cytoplasmic (CYT) domains are thought to directly interact to constrain the integrin in an inactive state (2). Agonist-stimulated talin binding to the 3 CYT domain may relieve this constraint, inducing ␣IIb3 activation (3).The ␣IIb and 3 transmembrane domains are also in proximity when the integrin is inactive and separate upon integrin activation (4). Moreover, these domains readily undergo homomeric interactions in micelles (5), and both homomeric and heteromeric interactions have been detected in biological membranes (6, 7). Thus, in the platelet membrane where the concentration of these domains is high, the ␣IIb and 3 helices might be expected to form homooligomers in the activated state, crosslinking individual molecules and stabilizing focal adhesions (8). Indeed, we tested this possibility previously by placing Asn, a residue known to strengthen homomeric transmembrane (TM) interactions (9, 10), at successive positions across a 10-residue segment of the 3 TM domain and found that mutations along one face of the helix led to constitutive ␣IIb3 activation and integrin clustering (11).However, there are two distinct mechanisms by which TM domain mutations might activate integrins. Besides increasing the tendency of a highly expressed integrin to form homooligomers, TM domain ...
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