Prediction of CASP6 structures using automated robetta protocols

Chivian, Dylan; Kim, David E.; Malmström, Lars; Schonbrun, Jack; Rohl, Carol A.; Baker, David

doi:10.1002/prot.20733

Cited by 134 publications

(104 citation statements)

References 47 publications

(71 reference statements)

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“…This modeling method is informatics-based, using the structures in the Protein Data Bank to predict the folding of each segment of the protein of interest and then assembling the most favored structure based on all known protein structures (47,48). The Rosetta method has been the most accurate in predicting the structures of folded domains in the critical assessment of techniques for protein structure prediction (CASP) trials of modeling (53,54). Moreover, we have recently developed a membrane mode of Rosetta that successfully predicts the transmembrane folds of 15 membrane proteins (55).…”

Section: Resultsmentioning

confidence: 99%

Structure and Function of the Voltage Sensor of Sodium Channels Probed by a β-Scorpion Toxin

Cestèle

Yarov‐Yarovoy²,

Qu³

et al. 2006

Journal of Biological Chemistry

135

166

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The voltage-gated ion channels and their structural relatives are a large superfamily of membrane proteins specialized for electrical signaling and ionic homeostasis (1). Voltage-gated sodium channels are responsible for the increase in sodium permeability that initiates action potentials in electrically excitable cells (2) and are the molecular target for several groups of neurotoxins, which bind to different receptor sites and alter voltage-dependent activation, conductance, and inactivation (3, 4). Sodium channels are composed of one pore-forming ␣ subunit of ϳ2000 amino acid residues associated with one or two smaller auxiliary subunits, ␤1-␤4 (5-7). The ␣ subunit consists of four homologous domains (I-IV), each containing six transmembrane segments (S1-S6), and a re-entrant pore loop (P) between S5 and S6 (5). The S4 transmembrane segments are positively charged and serve as voltage sensors to initiate channel activation (8 -14). However, the molecular mechanism of voltage sensing by sodium channels and the other members of the voltage-gated ion channel family is unknown.The initial "sliding helix" (9) or "helical screw" (15) models for voltage sensing proposed that the S4 segments, which have positively charged amino acids at intervals of three residues, transport gating charges outward to activate sodium channels in response to depolarization by moving along a spiral pathway through the protein structure. This movement would preserve interactions with surrounding hydrophilic and negatively charged amino acid residues during gating and thereby stabilize the gating charges in the intramembrane environment. Many structure-function studies have supported this general model (see "Discussion"). In contrast, x-ray crystallographic studies of a bacterial voltage-gated K ϩ channel in complex with detergent and a site-directed antibody yielded a structure in which the S3 and S4 segments lay along the position of the intracellular surface of the membrane, dissociated from the remainder of the protein (16 -18). These results led to the concept that the voltage sensors function as loosely linked "paddles," pivoting through the phospholipid surrounding the core of the ion channel as a semi-rigid body rather than moving gating charge outward through the protein structure. This paddle model makes strikingly different predictions for polypeptide toxins that modify gating by interaction with the voltage sensors. Whereas polypeptide toxins might be able to bind the extracellular end of the voltage sensors in the resting state in a sliding helix or helical screw gating model, the S4 segments would not be expected to be available for toxin binding in the resting state in the paddle model.Scorpion venoms contain two groups of polypeptides toxins that alter sodium channel gating. The ␣-scorpion toxins, as well as sea anemone toxins and some spider toxins, bind to neurotoxin receptor site 3 and slow or block inactivation (19 -22). Amino acid residues that contribute to neurotoxin receptor site

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Section: Resultsmentioning

confidence: 99%

Structure and Function of the Voltage Sensor of Sodium Channels Probed by a β-Scorpion Toxin

Cestèle

Yarov‐Yarovoy²,

Qu³

et al. 2006

Journal of Biological Chemistry

135

166

View full text Add to dashboard Cite

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“…Sequences were aligned using MUSCLE (Edgar, 2004) and edited manually. Alignment annotation was done in Jalview (Waterhouse et al, 2009) and secondary structure annotation of Nogo-66 alignment by Robetta (Chivian et al, 2005). Secondary structure annotation of NgR was performed based on Pfam (Finn et al, 2008), UniProt (Jain et al, 2009), and SMART (Letunic et al, 2006) feature data.…”

Section: Methodsmentioning

confidence: 99%

No Nogo66- and NgR-Mediated Inhibition of Regenerating Axons in the Zebrafish Optic Nerve

Abdesselem¹,

Shypitsyna²,

Solis³

et al. 2009

J. Neurosci.

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In contrast to mammals, lesioned axons in the zebrafish (ZF) optic nerve regenerate and restore vision. This correlates with the absence of the NogoA-specific N-terminal domains from the ZF nogo/rtn-4 (reticulon-4) gene that inhibits regeneration in mammals. However, mammalian nogo/rtn-4 carries a second inhibitory C-terminal domain, Nogo-66, being 70% identical with ZF-Nogo66. The present study examines, (1) whether ZF-Nogo66 is inhibitory and effecting similar signaling pathways upon Nogo66-binding to the Nogo66 receptor NgR and its coreceptors, and (2) whether Rat-Nogo66 on fish, and ZF-Nogo66 on mouse neurons, cause inhibition via NgR. Our results from "outgrowth, collapse and contact assays" suggest, surprisingly, that ZF-Nogo66 is growth-permissive for ZF and mouse neurons, quite in contrast to its Rat-Nogo66 homolog which inhibits growth. The opposite effects of ZF-and Rat-Nogo66 are, in both fish and mouse, transmitted by GPI (glycosylphosphatidylinositol)-anchored receptors, including NgR. The high degree of sequence homology in the predicted binding site is consistent with the ability of ZF-and mammalian-Nogo66 to bind to NgRs of both species. Yet, Rat-Nogo66 elicits phosphorylation of the downstream effector cofilin whereas ZF-Nogo66 has no influence on cofilin phosphorylation-probably because of significantly different Rat-versus ZF-Nogo66 sequences outside of the receptor-binding region effecting, by speculation, recruitment of a different set of coreceptors or microdomain association of NgR. Thus, not only was the NogoA-specific domain lost in fish, but Nogo66, the second inhibitory domain in mammals, and its signaling upon binding to NgR, was modified so that ZF-Nogo/RTN-4 does not impair axon regeneration.

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“…The 3D models developed by Robetta used the incretin hormone, gastric inhibitory peptide (GIP; PDB:2B4N) as a reference parent. The Ginzu module (Chivian et al 2005) parsed proglucagon into two domains, each using GIP as a reference parent. The N-terminal domain (aa 1-77) (PDB:2B4N) had a confidence of 5.40 by position-specific iterated BLAST (PSI-BLAST; Altschul et al 1990); the C-terminal domain (aa 78-158) (PDB:2OBU) had a confidence of 2.33 by HH-Search (Soding 2005).…”

Section: Protein Modellingmentioning

confidence: 99%

The sorting of proglucagon to secretory granules is mediated by carboxypeptidase E and intrinsic sorting signals

McGirr

Guizzetti

Dhanvantari

2013

Journal of Endocrinology

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Proglucagon is expressed in pancreatic alpha cells, intestinal L cells and brainstem neurons. Tissue-specific processing of proglucagon yields the peptide hormones glucagon in the alpha cell and glucagon-like peptide (GLP)-1 and GLP-2 in L cells. Both glucagon and GLP-1 are secreted in response to nutritional status and are critical for regulating glycaemia. The sorting of proglucagon to the dense-core secretory granules of the regulated secretory pathway is essential for the appropriate secretion of glucagon and GLP-1. We examined the roles of carboxypeptidase E (CPE), a prohormone sorting receptor, the processing enzymes PC1/3 and PC2 and putative intrinsic sorting signals in proglucagon sorting. In Neuro 2a cells that lacked CPE, PC1/3 and PC2, proglucagon co-localised with the Golgi marker p115 as determined by quantitative immunofluorescence microscopy. Expression of CPE, but not of PC1/3 or PC2, enhanced proglucagon sorting to granules. siRNA-mediated knockdown of CPE disrupted regulated secretion of glucagon from pancreatic-derived alphaTC1-6 cells, but not of GLP-1 from intestinal cell-derived GLUTag cells. Mutation of the PC cleavage site K70R71, the dibasic R17R18 site within glucagon or the alpha-helix of glucagon, all significantly affected the sub-cellular localisation of proglucagon. Protein modelling revealed that alpha helices corresponding to glucagon, GLP-1 and GLP-2, are arranged within a disordered structure, suggesting some flexibility in the sorting mechanism. We conclude that there are multiple mechanisms for sorting proglucagon to the regulated secretory pathway, including a role for CPE in pancreatic alpha cells, initial cleavage at K70R71 and multiple sorting signals.

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Prediction of CASP6 structures using automated robetta protocols

Cited by 134 publications

References 47 publications

Structure and Function of the Voltage Sensor of Sodium Channels Probed by a β-Scorpion Toxin

Structure and Function of the Voltage Sensor of Sodium Channels Probed by a β-Scorpion Toxin

No Nogo66- and NgR-Mediated Inhibition of Regenerating Axons in the Zebrafish Optic Nerve

The sorting of proglucagon to secretory granules is mediated by carboxypeptidase E and intrinsic sorting signals

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