Integrin cell-adhesion receptors transduce signals bidirectionally across the plasma membrane via the single-pass transmembrane segments of each ␣ and  subunit. While the 3 transmembrane segment consists of a linear 29-residue ␣-helix, the structure of the ␣IIb transmembrane segment reveals a linear 24-residue ␣-helix (Ile-966 -Lys-989) followed by a backbone reversal that packs Phe-992-Phe-993 against the transmembrane helix. The length of the ␣IIb transmembrane helix implies the absence of a significant transmembrane helix tilt in contrast to its partnering 3 subunit. Sequence alignment shows Gly-991-Phe-993 to be fully conserved among all 18 human integrin ␣ subunits, suggesting that their unusual structural motif is prototypical for integrin ␣ subunits. The ␣IIb transmembrane structure demonstrates a level of complexity within the membrane that is beyond simple transmembrane helices and forms the structural basis for assessing the extent of structural and topological rearrangements upon ␣IIb-3 association, i.e. integrin transmembrane signaling.Integrins are a major class of adhesion receptors that mediate cell migration and extracellular matrix assembly, as well as inflammation, thrombosis, and tumor metastasis (1). In addition to responding to signals that originate inside the cell and regulate receptor affinity, integrins can respond to the binding of extracellular ligands by activating intracellular signaling pathways (1). Integrins are noncovalent heterodimers with large extracellular and small intracellular domains that are connected by single-pass transmembrane (TM) 3 segments. An extensive set of experiments provides evidence that signals are transduced bidirectionally across the plasma membrane via the TM segments of the ␣ and  subunits (2-4). Specifically, the inactive receptor state is stabilized by the hydrophobic packing of the TM helices and adjacent electrostatic ␣IIb-3 interactions, whereas integrin activation ensues from the separation of the TM segments (2, 4 -8). However, the precise structural and topological processes underlying integrin inside-out and outside-in signaling events are currently unknown.Single-pass TM segments likely traverse the membrane as ␣-helices. The recently determined structure of the integrin 3 TM segment reconstituted in small bicelles fulfills this expectation, but the TM helix is not restricted to residues between the first charged residues, Asp-692 and Lys-716, on the extraand intracellular sides, respectively (9). Rather, the five mostly hydrophobic residues following Lys-716 are part of the 29-residue TM helix, encoding a substantial helix tilt relative to the membrane. Apparently, this allows Lys-716 to snorkel its side chain out of the hydrophobic lipid core. Integrin ␣ subunits exhibit a similar pattern of hydrophobicity; a lysine residue constitutes the first charged residue on the intracellular side and is followed by four mostly apolar residues (see Fig. 1). Nevertheless, the structure of the ␣IIb TM segment reported herein shows that the TM heli...
The 140-residue protein alpha-synuclein (aS) has been implicated in the molecular chain of events leading to Parkinson's disease, which relates to the hierarchical aggregation of aS into soluble oligomers and insoluble fibrils. A number of small organic molecules have been reported to inhibit aS aggregation. Here, the interactions of chlorazole black E, Congo red, lacmoid, PcTS-Cu (2+), and rosmarinic acid with aS are examined by NMR spectroscopy to identify aS sequence elements that are masked by these compounds. Surprisingly, similar aS interaction sites, encompassing residues 3-18 and 38-51, were obtained for all molecules at equimolar small molecule:aS ratios. At higher ratios, virtually the entire amphiphilic region of aS (residues 2-92) is affected, revealing the presence of additional, lower affinity interaction sites. Upon rearranging the high-affinity interaction sites over the aS amphiphilic region in an aS mutant form, perturbations of the entire amphiphilic region were found to have already been obtained at equimolar ratios, indicating a high specificity for the original binding sites. CD spectroscopy reveals that, in the presence of the small molecules, the aS structure is still dominated by random-coil characteristics. The strongest effects are exerted by molecules that contain sulfonate groups adjacent to aromatic systems, often present in multiple copies in a symmetrical arrangement, suggesting that these elements are useful for developing an aS-specific chemical chaperone.
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