Using multiple structure alignments, fast model building, and energetic analysis in fold recognition and homology modeling

Petrey, Donald; Xiang, Zhaoyin; Tang, Christopher L.; Xie, Lei; Gimpelev, Marina; Mitros, Therese; Soto, Cinque; Goldsmith-Fischman, Sharon; Kernytsky, Andrew; Schlessinger, Avner; Koh, Ingrid Y.Y.; Alexov, Emil; Honig, Barry

doi:10.1002/prot.10550

Cited by 286 publications

(264 citation statements)

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“…In detail, the amino acid sequence alignment between PSD-1 and GB1 (ref. 22) was used to build the model of the hypothetical 4b1a form of PSD-1 using the homology modeling program NEST (23). Then, flexible docking simulations were used to dock a Myr molecule onto both the a-helical form of the GA module PSD-1 (PDB code 2FS1) (24) and the modeled 4b1a form.…”

Section: Discussionmentioning

confidence: 99%

GA/GB Fold switching may modulate fatty acid transfer from human serum albumin to bacteria

et al. 2012

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Human serum albumin (HSA) accounts for most of the functions of plasma. Among others, HSA serves as a carrier and a solubilizer for many endogenous and exogenous ligands, including fatty acids (FAs) as well as peptides and proteins such as the GA module of the bacterial poly(A)‐binding (PAB) protein. Although the biological function(s) of the GA module of the bacterial PAB protein is unknown, the acquisition of the GA module adds selective advantages to the bacterium in terms of growth rate and increase in virulence, probably by providing the bacteria with FAs and, possibly, other nutrients transported by HSA. Here, we hypothesize that the GA module may undergo a structural transition from the all‐α form to the 4β+α form typical of the GB domains upon binding of a FA molecule, as part of the mechanism which allows the bacterial PAB protein to extract FAs from HSA. © 2012 IUBMB. IUBMB Life, 64(11): 885–888, 2012

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Section: Discussionmentioning

confidence: 99%

GA/GB Fold switching may modulate fatty acid transfer from human serum albumin to bacteria

et al. 2012

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“…The NL1 and NL3 sequences were first aligned to NL2 with T-COFFEE (35), and the resulting alignments were given as input to the NEST homology modeling program with default parameters (36). Electrostatic calculations were carried out with the program GRASP (26).…”

Section: Methodsmentioning

confidence: 99%

Crystal structure of the extracellular cholinesterase-like domain from neuroligin-2

Koehnke

Jin

Budreck

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Neuroligins (NLs) are catalytically inactive members of a family of cholinesterase-like transmembrane proteins that mediate cell adhesion at neuronal synapses. Postsynaptic neuroligins engage in Ca 2؉ -dependent transsynaptic interactions via their extracellular cholinesterase domain with presynaptic neurexins (NRXs). These interactions may be regulated by two short splice insertions (termed A and B) in the NL cholinesterase domain. Here, we present the 3.3-Å crystal structure of the ectodomain from NL2 containing splice insertion A (NL2A). The overall structure of NL2A resembles that of cholinesterases, but several structural features are unique to the NL proteins. First, structural elements surrounding the esterase active-site region differ significantly between active esterases and NL2A. On the opposite surface of the NL2A molecule, the positions of the A and B splice insertions identify a candidate NRX interaction site of the NL protein. Finally, sequence comparisons of NL isoforms allow for mapping the location of residues of previously identified mutations in NL3 and NL4 found in patients with autism spectrum disorders. Overall, the NL2 structure promises to provide a valuable model for dissecting NL isoform-and synapse-specific functions.acetylcholinesterase-like ͉ neurexin

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“…Secondary structure prediction programs predict, with low confidence, that this region is either unstructured or partially ␣-helical (40 -42). We used both Modeler6 (43) and Nest (44) to construct models for the FENS-1 FYVE domain based on the alignment extracted from the multiple sequence alignment. We implemented the loop prediction modules that are offered by both programs (45,46).…”

Section: Methodsmentioning

confidence: 99%

The Molecular Basis of the Differential Subcellular Localization of FYVE Domains

Blatner

Stahelin

Diraviyam

et al. 2004

Journal of Biological Chemistry

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This study systematically analyzed the structural and mechanistic basis of the regulation of subcellular membrane targeting using FYVE domains as a model. FYVE domains, which mediate the recruitment of signaling and membrane-trafficking proteins to phosphatidylinositol 3-phosphate-containing endosomes, exhibit distinct subcellular localization despite minor structural variations within the family. Biophysical measurements, cellular imaging, and computational analysis of various FYVE domains showed that the introduction of a single cationic residue and a hydrophobic loop into the membrane binding region of the FYVE domains dramatically enhanced their membrane interactions. The results indicated that there is a threshold affinity for endosomal localization and that endosomal targeting of FYVE domains is sensitive to small changes in membrane affinity about this threshold. Collectively these studies provide new insight into how subcellular localization of FYVE domains and other membrane targeting domains can be regulated by minimal structural and environmental changes.Numerous cellular processes such as signal transduction, vesicle trafficking, and cytoskeletal rearrangement require the exquisite targeting of peripheral proteins to various subcellular membranes. A large portion of this cellular membrane targeting is achieved by specific recognition of particular membrane lipids by proteins. A diverse group of membrane-targeting domains that specifically recognize different types of membrane lipids have been identified in the past decade. They include Bin Amphiphysin Rvs (BAR) (1), protein kinase C Conserved 1 (C1) (2, 3), protein kinase C Conserved 2 (C2) (4), Epsin AminoTerminal Homology (ENTH) (5), Band 4.1/Ezrin/Radixin/Moesin (FERM) (6), Fab1/YOTB/Vac1/EEA1 (FYVE) (7-11), Postsynaptic density-95/Discs large/ZO-1 (PDZ) (12), Pleckstrin Homology (PH) (13), Phosphotyrosine Binding (PTB) (14), Phox (PX) (15), Src homology 2 (SH2) (16), and tubby domains (17). Except for the C1 domain that binds diacylglycerol, these domains recognize phosphorylated derivatives of phosphatidylinositol, collectively known as phosphoinositides. Although much is known about the structural basis of stereospecific lipid head group recognition by these domains, less is known about the mechanisms by which they achieve efficient and reversible binding to the cell membranes containing their lipid ligands. In particular, there is much to learn about the structural and mechanistic basis of the regulation of the targeting of lipidinteracting domains to different intracellular membranes. Among various membrane-targeting domains, the FYVE domain serves as an excellent model to address these questions. This is because FYVE domains from different proteins exhibit drastically different subcellular localization behaviors (18 -22) despite the fact almost all FYVE domains show high specificity and affinity for phosphatidylinositol 3-phosphate (PtdIns(3)P). 1 FYVE domains are zinc-containing modules of 60 -80 amino acid residues (7-11). As expected fr...

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Using multiple structure alignments, fast model building, and energetic analysis in fold recognition and homology modeling

Cited by 286 publications

References 10 publications

GA/GB Fold switching may modulate fatty acid transfer from human serum albumin to bacteria

GA/GB Fold switching may modulate fatty acid transfer from human serum albumin to bacteria

Crystal structure of the extracellular cholinesterase-like domain from neuroligin-2

The Molecular Basis of the Differential Subcellular Localization of FYVE Domains

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