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PubMed1993

Noncoded residues as building blocks in the design of specific secondary structures: symmetrically disubstituted glycines and beta-alanine.

Structural changes can be induced in a peptide by selective substitution of coded alpha-amino acid residues by noncoded alpha-amino acid residues and the consequent production of analogues with modified structure and conformational preferences. In this review article we summarize the solid state structural results and the conformational preferences of two classes of "building blocks": (a) the linear and cyclic symmetrically alpha, alpha-disubstituted glycines in which either two identical n-alkyl groups replace the hydrogen atoms of the glycine residue or a cyclic aliphatic side-chain system is formed by linking the two alpha-carbon side chains, respectively; and (b) the beta-alanine residue. Examples, whenever possible, of the use of these residues for the elucidation of the bioactive conformation in the appropriate biological systems will be given.

Amino Acid Sequence↗
PubMed1995

Influence of proline-14 substitution on the secondary structure in a synthetic analogue of alamethicin.

Due to the bend introduced by proline 14 in the conformation of alamethicin (AcUPUAUAQUVUGLUPV UUEQFol), the role of this residue was assumed essential in the barrel-stave model for voltage-gated ion channels. Taking advantage of a previous synthetic alamethicin analogue (L2), in which all eight alpha-aminoisobutyric (U) were replaced by leucines (AcLPLALAQLV LGLLPV LLEQFol), another analogue (L5) was synthesized in order to test the effects of proline-14 substitution by an alanine (AcLPLALAQLVLGLLPVLLEQFol). Previous conductance experiments showed that both high voltage dependence and multistate behavior were conserved. In order to complement these functional results, a conformational study of L5 has been undertaken and compared to L2 using CD, high field nmr, and molecular dynamics. Results show that L5 presents a better ordered structure than L2 particularly in the region of the substitution and in the C-terminal part. These results are discussed as regards the previous hypothesis of the nonessential character of helix bending for the gating of voltage-dependent ion channels.

Alamethicin↗
PubMed2003

Assembling novel protein folds from super-secondary structural fragments.

The results of applying a fragment-based protein tertiary structure prediction method to the prediction of 14 CASP5 target domains are described. The method is based on the assembly of supersecondary structural fragments taken from highly resolved protein structures using a simulated annealing algorithm. A number of good predictions for proteins with novel folds were produced, although not always as the first model. For two fold recognition targets, FRAGFOLD produced the most accurate model in both cases, despite the fact that the predictions were not based on a template structure. Although clear progress has been made in improving FRAGFOLD since CASP4, the ranking of final models still seems to be the main problem that needs to be addressed before the next CASP experiment.

Algorithms↗
PubMed2005

Does secondary structure determine tertiary structure in proteins?

Is highly approximate knowledge of a protein's backbone structure sufficient to successfully identify its family, superfamily, and tertiary fold? To explore this question, backbone dihedral angles were extracted from the known three-dimensional structure of 2,439 proteins and mapped into 36 labeled, 60 degrees x 60 degrees bins, called mesostates. Using this coarse-grained mapping, protein conformation can be approximated by a linear sequence of mesostates. These linear strings can then be aligned and assessed by conventional sequence-comparison methods. We report that the mesostate sequence is sufficient to recognize a protein's family, superfamily, and fold with good fidelity.

Algorithms↗
PubMed2001

Role of the connectivity of secondary structure segments in the folding of alpha(1)-antitrypsin.

The native form of serpins (serine protease inhibitors) is metastable, which is critical to their biological functions. Spontaneous conversion from the native form of serpins into a more stable conformation, called the "latent" form, is restricted. To examine whether the connectivity of strand 1 of beta-sheet C to the hydrophobic core is critical to the serpin's preferential folding to the metastable native conformation, we designed a circularly-permuted mutant of alpha(1)-antitrypsin, the prototype serpin, in which strand 1C is disconnected from the hydrophobic core. Conformation of the circular permutant was similar to that of the latent form, as revealed by equilibrium unfolding, limited proteolysis, and spectroscopic properties. Our results support the notion that rapid folding of the hydrophobic core with concomitant incorporation of strand 1C into beta-sheet C traps the serpin molecule into its native metastable conformation.

Circular Dichroism↗
PubMed1993

Packing of secondary structural elements in proteins. Analysis and prediction of inter-helix distances.

Interacting helix pairs were defined as those in which each member has one residue which undergoes a fractional loss of 0.10 solvent accessible contact area on association. Analysis of 1095 such pairs of helices, selected from the Brookhaven Data Bank, confirms that helix pairs in proteins can pack interactively at all angles with preferential packing observed in the angle intervals (omega), -160 degrees to -140 degrees, -100 degrees to -20 degrees, 10 degrees to 40 degrees, and 50 degrees to 160 degrees. The distance (d) between the helix axes in the contact region of two interactively packed helices is linearly correlated with the volume-dependent function, log(V/nda), of the residues in this region. The correlation is used to predict inter-helix distances in equivalent helix pairs of homologous proteins and is therefore of value in comparative modelling of protein three-dimensional structures.

Amino Acid Sequence↗
PubMed2004

Secondary structure, phospholipid membrane interactions, and fusion activity of two glutamate-rich analogs of influenza hemagglutinin fusion peptide.

Two synthetic mutants of influenza HA2 fusion peptide (residues 1-25), containing Glu on the polar (residues 4,8-E5(4,8)) or the hydrophobic (residues 3,7-E5(3,7)) face of the amphipathic helix, were synthesized and labeled with NBD at the N-terminus. Introduction of Glu residues into the fusion peptide leads to increased sensitivity of various biochemical properties to pH compared to the wild type. The E5 peptides showed a decrease of alpha-helix content and increase of beta-sheet structure. Lipid binding was diminished, but not abolished even at high pH. The E5 analogs penetrate the lipid bilayer less deeply than the wild type, especially at high pH. The N-terminal half of the peptide showed significant variation of the depth of the penetration into the lipid bilayer. Both E5 peptides were fusion active. The properties of E5(3,7) were more affected by the Glu substitution and showed greater variation with pH than E5(4,8).

Binding Sites↗
PubMed2002

Determination of the secondary structure in solution of the Escherichia coli DnaA DNA-binding domain.

DnaA protein binds specifically to a group of binding sites collectively called as DnaA boxes within the bacterial replication origin to induce local unwinding of duplex DNA. The DNA-binding domain of DnaA, domain IV, comprises the C-terminal 94 amino acid residues of the protein. We overproduced and purified a protein containing only this domain plus a methionine residue. This protein was stable as a monomer and maintained DnaA box-specific binding activity. We then analyzed its solution structure by CD spectrum and heteronuclear multi-dimensional NMR experiments. We established extensive assignments of the 1H, 13C, and 15N nuclei, and revealed by obtaining combined analyses of chemical shift index and NOE connectivities that DnaA domain IV contains six alpha-helices and no beta-sheets, consistent with results of CD analysis. Mutations known to reduce DnaA box-binding activity were specifically located in or near two of the alpha-helices. These findings indicate that the DNA-binding fold of DnaA domain IV is unique among origin-binding proteins.

Amino Acid Sequence↗
PubMed2002

Heteronuclear NMR studies of human serum apolipoprotein A-I. Part I. Secondary structure in lipid-mimetic solution.

The apolipoprotein A-I (apoA-I) solution structure in the presence of sodium dodecyl sulfate (SDS) was determined by combination of chemical shift index and torsion angle likelihood obtained from shift and sequence similarity methods. ApoA-I in lipid-mimetic solution is composed of alpha-helices (residues 8-32, 45-64, 67-77, 82-86, 90-97, 100-118, 122-140, 146-162, 167-205, 210-216 and 221-239), with 2-5 residue irregular segments between helical repeats, and the irregular segment 78-81 within helical repeat 2. ApoA-I is a monomer in the SDS complex and no evidence of interhelical interactions is found. Comparison of the apoA-I and apoA-I(1-186) [Okon et al., FEBS Lett. 487 (2001) 390-396] solution structures revealed that apoA-I undergoes a conformational change around Pro121.

Apolipoprotein A-I↗
PubMed1998

Secondary structure of the membrane-bound domains of H+,K+-ATPase and Ca2+-ATPase, a comparison by FTIR after proteolysis treatment of the native membranes.

The sarcoplasmic reticulum Ca2+-ATPase and the gastric H+,K+-ATPase were cleaved under three different proteolysis conditions. After elimination of the protease and of the cleaved peptides, the vesicles containing the membrane-bound peptides of the ATPases were studied by Fourier transform attenuated total reflection infrared spectroscopy. In the harsher proteolysis conditions, the membrane-associated domain of the Ca2+-ATPase represented about 20% of the protein and was mainly constituted of alpha-helices. Polarized infrared spectroscopy showed that these alpha-helices were mainly oriented perpendicular to the membrane. However, only 10-20% of the H+,K+-ATPase was cleaved. The remaining, membrane-associated domain of the protein contained about 30% of alpha-helices and 30% of beta-sheet structures. The alpha-helices adopted a mainly transmembrane orientation. While the data on the Ca2+-ATPase are in general agreement with the current model of the protein, our results indicate that caution must be used in choosing this protein as a general structural model for all P-type ATPases. The protease-resistant, membrane-associated domain of the H+K+-ATPase is indeed much larger than predicted and also contained beta-sheet structures.

Adenosine Triphosphate↗
PubMed1999

NMR assignments and secondary structure of the UvrC binding domain of UvrB.

The 55 residue C-terminal domain of UvrB that interacts with UvrC during excision repair in Escherichia coli has been expressed and purified as a (His)6 fusion construct. The fragment forms a stable folded domain in solution. Heteronuclear NMR experiments were used to obtain extensive 15N, 13C and 1H NMR assignments. NOESY and chemical shift data showed that the protein comprises two helices from residues 630 to 648 and from 652 to 670. 15N relaxation data also show that the first 11 and last three residues are unstructured. The effective rotational correlation time within the structured region is not consistent with a monomer. This oligomerisation may be relevant to the mode of dimerisation of UvrB with the homologous domain of UvrC.

Amino Acid Sequence↗
PubMed1998

A combinatorial distance-constraint approach to predicting protein tertiary models from known secondary structure.

BACKGROUND: Distance geometry methods allow protein structures to be constructed using a large number of distance constraints, which can be elucidated by experimental techniques such as NMR. New methods for gleaning tertiary structural information from multiple sequence alignments make it possible for distance constraints to be predicted from sequence information alone. The basic distance geometry method can thus be applied using these empirically derived distance constraints. Such an approach, which incorporates a novel combinatoric procedure, is reported here. RESULTS: Given the correct sheet topology and disulfide formations, the fully automated procedure is generally able to construct native-like Calpha models for eight small beta-protein structures. When the sheet topology was unknown but disulfide connectivities were included, all sheet topologies were explored by the combinatorial procedure. Using a simple geometric evaluation scheme, models with the correct sheet topology were ranked first in four of the eight example cases, second in three examples and third in one example. If neither the sheet topology nor the disulfide connectivities were given a priori, all combinations of sheet topologies and disulfides were explored by the combinatorial procedure. The evaluation scheme ranked the correct topology within the top five folds for half the example cases. CONCLUSIONS: The combinatorial procedure is a useful technique for identifying a limited number of low-resolution candidate folds for small, disulfide-rich, beta-protein structures. Better results are obtained, however, if correct disulfide connectivities are known in advance. Combinatorial distance constraints can be applied whenever there are a sufficiently small number of finite connectivities.

Amino Acid Sequence↗
PubMed2002

A novel short neurotoxin, cobrotoxin c, from monocellate cobra (Naja kaouthia) venom: isolation and purification, primary and secondary structure determination, and tertiary structure modeling.

A novel short neurotoxin, cobrotoxin c (CBT C) was isolated from the venom of monocellate cobra (Naja kaouthia) using a combination of ion-exchange chromatography and FPLC. Its primary structure was determined by Edman degradation. CBT C is composed of 61 amino acid residues. It differs from cobrotoxin b (CBT B) by only two amino acid substitutions, Thr/Ala11 and Arg/Thr56, which are not located on the functionally important regions by sequence similarity. However, the LD50 is 0.08 mg/g to mice, i.e. approximately five-fold higher than for CBT B. Strikingly, a structure-function relationship analysis suggests the existence of a functionally important domain on the outside of Loop III of CBT C. The functionally important basic residues on the outside of Loop III might have a pairwise interaction with alpha subunit, instead of gamma or delta subunits of the nicotinic acetylcholine receptor (nAChR).

Amino Acid Sequence↗
PubMed1995

1H, 13C, and 15N NMR resonance assignments, secondary structure, and backbone topology of a variant of human interleukin-3.

Interleukin-3 (IL-3) is a cytokine which stimulates the proliferation and differentiation of hematopoietic progenitors into multiple cell lineages. The 1H, 15N, and 13C NMR resonances of a recombinant human IL-3 variant (SC-65369) have been assigned using two- and three-dimensional NMR techniques on uniformly 13C/15N-enriched protein. Five helical segments (residues 16-26, 42-50, 55-65, 73-82, and 104-120) and three reverse turns (residues 51-54, 68-71, and 87-90) were identified from the pattern of sequential NOE connectivities, NH(i)-C alpha H(i) scalar coupling constants (3JNH alpha), amide hydrogen exchange data, and the deviation of 13C alpha, 13C beta, 13CO, and C alpha H chemical shifts from random-coil values. Long-range NOEs indicate that the global folding pattern of human IL-3 is a four-helical bundle with an up-up-down-down arrangement of helices that is similar to that of other members of the cytokine family, such as granulocyte-macrophage colony stimulating factor (GM-CSF). A fifth short helix (helix A', residues 42-50) is located in the loop connecting the first and second helices. The absence of helix A' in the corresponding structures of GM-CSF and interleukin-5 suggests that it may be important for recognition of IL-3 by its receptor. The existence of at least two forms of the protein that differ in local conformation was implied from the observation of a limited set of doubled resonances in which each doublet partner had a similar pattern of short-, medium-, and long-range NOEs. The majority of the doubled resonances were close in sequence or space to a proline-rich sequence, which suggested that the different conformational forms of SC-65369 may be caused by slow cis-trans isomerization of proline peptide bonds.

Amino Acid Sequence↗
PubMed2000

The yeast mitochondrial citrate transport protein: determination of secondary structure and solvent accessibility of transmembrane domain IV using site-directed spin labeling.

To explore the spatial organization and functional dynamics of the citrate transport protein (CTP), a nitroxide scan was carried out along 22 consecutive residues within the fourth transmembrane domain (TMDIV). This domain has been implicated as being of unique importance to the CTP mechanism due to (i) the presence of two intramembranous positive charges that are essential for CTP function and (ii) the existence of a transmembrane aqueous surface within this domain which likely corresponds to a portion of the citrate translocation pathway. The sequence-specific variation in the mobilities of the introduced nitroxides and their accessibilities to molecular O(2) reveal an alpha-helical conformation along the sequence. The accessibilities to NiEDDA are out of phase with accessibilites to O(2), indicating that one face of the helix is solvated by the lipid bilayer while the other is solvated by an aqueous environment. A gradient of NiEDDA accessibility is observed along the helix surface facing the aqueous phase, and the EPR spectral line shapes at these sites indicate considerable motional restriction. In the context of the model where TMDIV lines the translocation pathway, these data suggest a barrier to passive diffusion through the pathway. This paper reports the first use of site-directed spin labeling to study mitochondrial transporter structure.

Amino Acid Sequence↗
PubMed1994

Assignments, secondary structure, global fold, and dynamics of chemotaxis Y protein using three- and four-dimensional heteronuclear (13C,15N) NMR spectroscopy.

NMR spectroscopy has been used to study recombinant Escherichia coli CheY, a 128-residue protein involved in regulating bacterial chemotaxis. Heteronuclear three- and four-dimensional (3D and 4D) experiments have provided sequence-specific resonance assignments and quantitation of short-, medium-, and long-range distance restraints from nuclear Overhauser enhancement (NOE) intensities. These distance restraints were further supplemented with measurements of three-bond scalar coupling constants to define the local dihedral angles, and with the identification of amide protons undergoing slow solvent exchange from which hydrogen-bonding patterns were identified. The current model structure shows the same global fold of CheY as existing X-ray structures (Volz & Matsumura, 1991; Stock et al. 1993) with a (beta/alpha)5 motif of five parallel beta-strands at the central core surrounded by three alpha-helices on one face and with two on the opposite side. Heteronuclear 15N-1H relaxation experiments are interpreted to show portions of the protein structure in the Mg2+ binding loop are ill-defined because of slow motion (chemical exchange) on the NMR time scale. Moreover, the presence of Mg2+ disrupts the salt bridge between the highly conserved Lys-109 and Asp-57, the site of phosphorylation.

Amino Acid Sequence↗