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388 results on '"Forrest, Lucy R."'

106. Structural fold and binding sites of the human Na⁺-phosphate cotransporter NaPi-II

Author

Fenollar-Ferrer, Cristina, Patti, Monica, Knöpfel, Thomas, Werner, Andreas, Forster, Ian C, Forrest, Lucy R, Fenollar-Ferrer, Cristina, Patti, Monica, Knöpfel, Thomas, Werner, Andreas, Forster, Ian C, and Forrest, Lucy R

Abstract

Phosphate plays essential biological roles and its plasma level in humans requires tight control to avoid bone loss (insufficiency) or vascular calcification (excess). Intestinal absorption and renal reabsorption of phosphate are mediated by members of the SLC34 family of sodium-coupled transporters (NaPi-IIa,b,c) whose membrane expression is regulated by various hormones, circulating proteins, and phosphate itself. Consequently, NaPi-II proteins are also potentially important pharmaceutical targets for controlling phosphate levels. Their crucial role in Pi homeostasis is underscored by pathologies resulting from naturally occurring SLC34 mutations and SLC34 knockout animals. SLC34 isoforms have been extensively studied with respect to transport mechanism and structure-function relationships; however, the three-dimensional structure is unknown. All SLC34 transporters share a duplicated motif comprising a glutamine followed by a stretch of threonine or serine residues, suggesting the presence of structural repeats as found in other transporter families. Nevertheless, standard bioinformatic approaches fail to clearly identify a suitable template for molecular modeling. Here, we used hydrophobicity profiles and hidden Markov models to define a structural repeat common to all SLC34 isoforms. Similar approaches identify a relationship with the core regions in a crystal structure of Vibrio cholerae Na(+)-dicarboxylate transporter VcINDY, from which we generated a homology model of human NaPi-IIa. The aforementioned SLC34 motifs in each repeat localize to the center of the model, and were predicted to form Na(+) and Pi coordination sites. Functional relevance of key amino acids was confirmed by biochemical and electrophysiological analysis of expressed, mutated transporters. Moreover, the validity of the predicted architecture is corroborated by extensive published structure-function studies. The model provides key information for elucidating the transport mechanism and pr

Published
2014

113. The Role of Sodium Sites in LeuT Conformational Changes

Author

Rudnick, Gary, primary, Tavoulari, Sotiria, additional, Zhang, Yuan-Wei, additional, DeWitt, David, additional, Nagarajan, Anu, additional, Rosado, Edwin, additional, Ravera, Silvia, additional, Kreuder, Anna-Elisabeth, additional, Forrest, Lucy R., additional, and Rhoades, Elizabeth, additional

Published
2014
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115. Alignment of helical membrane protein sequences using AlignMe

Author

Stamm, Marcus, Staritzbichler, René, Khafizov, Kamil, Forrest, Lucy R., Stamm, Marcus, Staritzbichler, René, Khafizov, Kamil, and Forrest, Lucy R.

Abstract

Few sequence alignment methods have been designed specifically for integral membrane proteins, even though these important proteins have distinct evolutionary and structural properties that might affect their alignments. Existing approaches typically consider membrane-related information either by using membrane-specific substitution matrices or by assigning distinct penalties for gap creation in transmembrane and non-transmembrane regions. Here, we ask whether favoring matching of predicted transmembrane segments within a standard dynamic programming algorithm can improve the accuracy of pairwise membrane protein sequence alignments. We tested various strategies using a specifically designed program called AlignMe. An updated set of homologous membrane protein structures, called HOMEP2, was used as a reference for optimizing the gap penalties. The best of the membrane-protein optimized approaches were then tested on an independent reference set of membrane protein sequence alignments from the BAliBASE collection. When secondary structure (S) matching was combined with evolutionary information (using a position-specific substitution matrix (P)), in an approach we called AlignMePS, the resultant pairwise alignments were typically among the most accurate over a broad range of sequence similarities when compared to available methods. Matching transmembrane predictions (T), in addition to evolutionary information, and secondary-structure predictions, in an approach called AlignMePST, generally reduces the accuracy of the alignments of closely-related proteins in the BAliBASE set relative to AlignMePS, but may be useful in cases of extremely distantly related proteins for which sequence information is less informative. The open source AlignMe code is available at https://sourceforge.net/projects/alignme​/, and at http://www.forrestlab.org, along with an online server and the HOMEP2 data set.

Published
2013

137. Membrane protein prediction methods

Author

Punta, Marco, primary, Forrest, Lucy R., additional, Bigelow, Henry, additional, Kernytsky, Andrew, additional, Liu, Jinfeng, additional, and Rost, Burkhard, additional

Published
2007
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