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Publications (3)20.11 Total impact

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    ABSTRACT: C99 (also known as β-CTF) is the 99 residue transmembrane C-terminal domain (residues 672-770) of the amyloid precursor protein and is the immediate precursor of the amyloid-β (Aβ) polypeptides. To test the dependence of the C99 structure on the composition of the host model membranes, NMR studies of C99 were conducted in both anionic lyso-myristoylphosphatidylglycerol (LMPG) micelles and in a series of five zwitterionic bicelle compositions involving phosphatidylcholine and sphingomyelin in which the acyl chain lengths of these lipid components varied from 14 to 24 carbons. Some of these mixtures are reported for the first time in this work and should be of broad utility in membrane protein research. The site-specific backbone 15N and 1H chemical shifts for C99 in LMPG and in all 5 bicelle mixtures were seen to be remarkably similar, indicating little dependence of the backbone structure of C99 on the com-position of the host model membrane. However, the length of the transmembrane span was seen to vary in a manner that alters the positioning of the gamma-secretase cleavage sites with respect to the center of the bilayer. This observation may contribute to the known dependency of the Aβ42-to-Aβ40 production ratio on both membrane thickness and the length of the C99 transmembrane domain.
    Journal of the American Chemical Society 02/2014; · 10.68 Impact Factor
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    ABSTRACT: From roughly 1985 through the start of the new millennium, the cutting edge of solution protein nuclear magnetic resonance (NMR) spectroscopy was to a significant extent driven by the aspiration to determine structures. Here we survey recent advances in protein NMR that herald a renaissance in which a number of its most important applications reflect the broad problem-solving capability displayed by this method during its classical era during the 1970s and early 1980s. Without receivers fitted and kept in order, the air may tingle and thrill with the message, but it will not reach my spirit and consciousness. Mary Slessor, Calabar, ca. 1910
    Biochemistry 01/2013; 52(8):1303-1320. · 3.38 Impact Factor
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    ABSTRACT: Loss of β1 integrin expression inhibits renal collecting-system development. Two highly conserved NPXY motifs in the distal β1 tail regulate integrin function by associating with phosphtyrosine binding (PTB) proteins, such as talin and kindlin. Here, we define the roles of these two tyrosines in collecting-system development and delineate the structural determinants of the distal β1 tail using nuclear magnetic resonance (NMR). Mice carrying alanine mutations have moderate renal collecting-system developmental abnormalities relative to β1-null mice. Phenylalanine mutations did not affect renal collecting-system development but increased susceptibility to renal injury. NMR spectra in bicelles showed the distal β1 tail is disordered and does not interact with the model membrane surface. Alanine or phenylalanine mutations did not alter β1 structure or interactions between α and β1 subunit transmembrane/cytoplasmic domains; however, they did decrease talin and kindlin binding. Thus, these studies highlight the fact that the functional roles of the NPXY motifs are organ dependent. Moreover, the β1 cytoplasmic tail, in the context of the adjacent transmembrane domain in bicelles, is significantly different from the more ordered, membrane-associated β3 integrin tail. Finally, tyrosine mutations of β1 NPXY motifs induce phenotypes by disrupting their interactions with critical integrin binding proteins like talins and kindlins.
    Molecular and cellular biology 08/2012; 32(20):4080-91. · 6.06 Impact Factor