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At least 19 recordsLinked to original sources
PubMed2006

Classification of protein quaternary structure by functional domain composition.

BACKGROUND: The number and the arrangement of subunits that form a protein are referred to as quaternary structure. Quaternary structure is an important protein attribute that is closely related to its function. Proteins with quaternary structure are called oligomeric proteins. Oligomeric proteins are involved in various biological processes, such as metabolism, signal transduction, and chromosome replication. Thus, it is highly desirable to develop some computational methods to automatically classify the quaternary structure of proteins from their sequences. RESULTS: To explore this problem, we adopted an approach based on the functional domain composition of proteins. Every protein was represented by a vector calculated from the domains in the PFAM database. The nearest neighbor algorithm (NNA) was used for classifying the quaternary structure of proteins from this information. The jackknife cross-validation test was performed on the non-redundant protein dataset in which the sequence identity was less than 25%. The overall success rate obtained is 75.17%. Additionally, to demonstrate the effectiveness of this method, we predicted the proteins in an independent dataset and achieved an overall success rate of 84.11% CONCLUSION: Compared with the amino acid composition method and Blast, the results indicate that the domain composition approach may be a more effective and promising high-throughput method in dealing with this complicated problem in bioinformatics.

Algorithms↗
PubMed2003

Classification of protein quaternary structure with support vector machine.

MOTIVATION: Since the gap between sharply increasing known sequences and slow accumulation of known structures is becoming large, an automatic classification process based on the primary sequences and known three-dimensional structure becomes indispensable. The classification of protein quaternary structure based on the primary sequences can provide some useful information for the biologists. So a fully automatic and reliable classification system is needed. This work tries to look for the effective methods of extracting attribute and the algorithm for classifying the quaternary structure from the primary sequences. RESULTS: Both of the support vector machine (SVM) and the covariant discriminant algorithms have been first introduced to predict quaternary structure properties from the protein primary sequences. The amino acid composition and the auto-correlation functions based on the amino acid index profile of the primary sequence have been taken into account in the algorithms. We have analyzed 472 amino acid indices and selected the four amino acid indices as the examples, which have the best performance. Thus the five attribute parameter data sets (COMP, FASG, NISK, WOLS and KYTJ) were established from the protein primary sequences. The COMP attribute data set is composed of amino acid composition, and the FASG, NISK, WOLS and KYTJ attribute data sets are composed of the amino acid composition and the auto-correlation functions of the corresponding amino acid residue index. The overall accuracies of SVM are 78.5, 87.5, 83.2, 81.7 and 81.9%, respectively, for COMP, FASG, NISK, WOLS and KYTJ data sets in jackknife test, which are 19.6, 7.8, 15.5, 13.1 and 15.8%, respectively, higher than that of the covariant discriminant algorithm in the same test. The results show that SVM may be applied to discriminate between the primary sequences of homodimers and non-homodimers and the two protein sequence descriptors can reflect the quaternary structure information. Compared with previous Robert Garian's investigation, the performance of SVM is almost equal to that of the Decision tree models, and the methods of extracting feature vector from the primary sequences are superior to Robert's binning function method. AVAILABILITY: Programs are available on request from the authors.

Algorithms↗
PubMed2005

Instrumental parameters in the MALDI-TOF mass spectrometric analysis of quaternary protein structures.

Several former studies have shown that MALDI-TOF-MS can be applied successfully to investigate the quaternary structure of proteins. Whereas most of these reports were focused on MALDI sample preparation, there is little information about the influence of instrumental parameters on the desorption/ionization and gas-phase behavior of protein subunit assemblies. Therefore, in addition of giving short examples of the quaternary structure analysis of a microheterogeneous glycoprotein, a metalloenzyme, and a heme-binding enzyme by MALDI-TOF-MS, we report a systematic study of the effect of some instrumental parameters on the analysis of chicken egg white avidin. From these tested parameters, only the laser pulse energy was found to influence the relative abundance of the intact assembly as well as the formation of nonspecific cluster ions significantly. This finding suggests that the disruption of the noncovalent interactions during the desorption/ionization process takes place at a very short time interval after the laser ablation, whereas those assemblies that survive this step are rather stable afterward in the gas phase. In addition, we present clear evidence that protein cluster ions are not preformed during sample preparation but originate from nonspecific assemblage during desorption/ionization.

Alcohol Dehydrogenase↗
PubMed2003

Predicting protein quaternary structure by pseudo amino acid composition.

In the protein universe, many proteins are composed of two or more polypeptide chains, generally referred to as subunits, that associate through noncovalent interactions and, occasionally, disulfide bonds. With the number of protein sequences entering into data banks rapidly increasing, we are confronted with a challenge: how to develop an automated method to identify the quaternary attribute for a new polypeptide chain (i.e., whether it is formed just as a monomer, or as a dimer, trimer, or any other oligomer). This is important, because the functions of proteins are closely related to their quaternary attribute. For example, some critical ligands only bind to dimers but not to monomers; some marvelous allosteric transitions only occur in tetramers but not other oligomers; and some ion channels are formed by tetramers, whereas others are formed by pentamers. To explore this problem, we adopted the pseudo amino acid composition originally proposed for improving the prediction of protein subcellular location (Chou, Proteins, 2001; 43:246-255). The advantage of using the pseudo amino acid composition to represent a protein is that it has paved a way that can take into account a considerable amount of sequence-order effects to significantly improve prediction quality. Results obtained by resubstitution, jack-knife, and independent data set tests, have indicated that the current approach might be quite promising in dealing with such an extremely complicated and difficult problem.

Algorithms↗
PubMed2003

Probabilistic approach to the design of symmetric protein quaternary structures.

Probabilistic methods have been developed that estimate the site-specific probabilities of the amino acids in sequences likely to fold to a particular target structure, and such information can be used to guide the de novo design of proteins and to probe sequence variability. An extension of these methods for the design of symmetric homo-oligomeric quaternary structures is presented. The theory is in excellent agreement with the results of studies on exactly solvable lattice models. Application to an atomically detailed representation of proteins verifies the utility of a symmetry assumption, which greatly simplifies and accelerates the calculations. The method may be applied to a wide variety of symmetric and periodic protein structures.

Amino Acids↗
PubMed2001

Effect of enzyme inhibitors on protein quaternary structure determined by on-line size exclusion chromatography-microelectrospray ionization mass spectrometry.

Aldehyde dehydrogenases (ALDH) are a family of enzymes primarily involved in the oxidation of various aldehydes. Most ALDH enzymes derived from mammalian sources have been shown to exist as homotetramers, consisting of four identical subunits of approximately 54 kDa. The presence of the homotetramer appears to be necessary for enzyme activity. In this study, recombinant rat liver mitochondrial ALDH (rmALDH) was inhibited in vitro with four different inhibitors, namely, disulfiram (MW, 296.5), prunetin (MW, 284.3), benomyl (MW, 290.3), and N-tosyl-L-phenylalanine chloromethyl ketone (TPCK) (MW, 351.8). Subsequently, inhibited rmALDH was analyzed by a novel approach of on-line size exclusion chromatography-microelectrospray ionization-mass spectrometry (SEC-muESI-MS) to examine the noncovalent quaternary structural stability of the inhibited enzyme. Analysis of native rmALDH by SEC-muESI-MS revealed predominantly the homotetramer (Mr = approximately 217,457 Da, +/- 0.01%) with some in-source, skimmer-induced dissociation to afford monomer (Mr = approximately 54,360 Da, +/- 0.01%). Both disulfiram and prunetin inhibited rmALDH by >70% and >90%, respectively, but did not disrupt the quaternary structure of rmALDH. Furthermore, there was no detectable change within experimental error (+/- 0.01%) of the disulfiram or the prunetin homotetramers (Mr = approximately 217,448 Da and Mr = approximately 217,446 Da). This may possibly indicate that inhibition occurred via formation of intramolecular disulfide bond at the enzyme active site, or weak affinity noncovalent binding. In contrast, benomyl-inhibited rmALDH homotetramer (>90% inhibition) exhibited a Mr = approximately 217,650 Da (+/- 0.01%) corresponding to two butylcarbamoyl adducts on two of the four enzyme subunits. The skimmer-induced monomer afforded a mixture of unmodified rmALDH (Mr = approximately 54,365 Da, +/- 0.01%) and butylcarbamoylated enzyme (Mr = approximately 54,459 Da, +/- 0.01%). Finally, TPCK (>90% inhibition) modified all four subunits of rmALDH to give Mr = approximately 218,646 Da (+/- 0.01%). In all four cases while significant enzyme inhibition occurred, no destabilization of the quaternary complex was detected.

Aldehyde Dehydrogenase↗
PubMed2005

Substrate-induced interconversion of protein quaternary structure isoforms.

Human porphobilinogen synthase (PBGS) can exist in two dramatically different quaternary structure isoforms, which have been proposed to be in dynamic equilibrium. The quaternary structure isoforms of PBGS result from two alternative conformations of the monomer; one monomer structure assembles into a high activity octamer, whereas the other monomer structure assembles into a low activity hexamer. The kinetic behavior of these oligomers led to the hypothesis that turnover facilitates the interconversion of the oligomeric structures. The current work demonstrates that the interactions of ligands at the enzyme active site promote the structural interconversion between human PBGS quaternary structure isoforms, favoring formation of the octamer. This observation illustrates that the assembly and disassembly of oligomeric proteins can be facilitated by the protein motions that accompany enzymatic catalysis.

Humans↗
PubMed2001

Analysis of rapid, large-scale protein quaternary structural changes: time-resolved X-ray solution scattering of Nudaurelia capensis omega virus (NomegaV) maturation.

Time-resolved small-angle X-ray scattering (TR-SAXS) was used to study the kinetics of a large conformational change that occurs during the maturation of an icosahedral virus. Virus-like particles (VLPs) of the T=4 non-enveloped RNA virus Nudaurelia capensis omega virus (NomegaV) were shown to undergo a large pH-dependent conformational change. Electron cryo-microscopy (cryoEM) and X-ray solution scattering were used to show that the precursor VLP (procapsid) was 16 % larger in diameter than the resulting capsid, which was shown by the cryoEM study to closely resemble the infectious mature virion. The procapsid form of the VLPs was observed at pH 7.5 and was converted to the capsid form at pH 5.0. Static SAXS measurements of the VLPs in solutions ranging between these pH values determined that the half-titration point of the transition was pH 6.0. Time-resolved SAXS experiments were performed on VLP solutions by initiating a pH change from 7.5 to 5.0 using a stopped-flow device, and the time-scale of the conformational change occurred in the subsecond range. Using a less drastic pH change (lowering the pH to 5.8 or 5.5), the conformational change occurred more slowly, on the subminute or minute time-scale, with the detection of a fast-forming intermediate in the transition. Further characterization using static SAXS measurements showed that the conformational change was initially reversible but became irreversible after autoproteolytic maturation was about 15 % complete. In addition to characterizing the large quaternary conformational change, we have been able for the first time to demonstrate that it takes place on the subsecond time-scale, a regime comparable to that observed in other multisubunit assemblies.

Capsid↗
PubMed2005

Low resolution structural study of two human HSP40 chaperones in solution. DJA1 from subfamily A and DJB4 from subfamily B have different quaternary structures.

Proteins that belong to the heat shock protein (Hsp) 40 family assist Hsp70 in many cellular functions and are important for maintaining cell viability. A knowledge of the structural and functional characteristics of the Hsp40 family is therefore essential for understanding the role of the Hsp70 chaperone system in cells. In this work, we used small angle x-ray scattering and analytical ultracentrifugation to study two representatives of human Hsp40, namely, DjA1 (Hdj2/dj2/HSDJ/Rdj1) from subfamily A and DjB4 (Hlj1/DnaJW) from subfamily B, and to determine their quaternary structure. We also constructed low resolution models for the structure of DjA1-(1-332), a C-terminal-deleted mutant of DjA1 in which dimer formation is prevented. Our results, together with the current structural information of the Hsp40 C-terminal and J-domains, were used to generate models of the internal structural organization of DjA1 and DjB4. The characteristics of these models indicated that DjA1 and DjB4 were both dimers, but with substantial differences in their quaternary structures: whereas DjA1 consisted of a compact dimer in which the N and C termini of the two monomers faced each other, DjB4 formed a dimer in which only the C termini of the two monomers were in contact. The two proteins also differed in their ability to bind unfolded luciferase. Overall, our results indicate that these representatives of subfamilies A and B of human Hsp40 have different quaternary structures and chaperone functions.

Amino Acid Sequence↗
PubMed1986

Co-operativity value of DNA RecA protein interaction. Influence of the protein quaternary structure on the binding analysis.

We show that an erroneous estimation of the quaternary structure of free protein distorts the quantitative analysis of its interaction with DNA, affecting especially the co-operativity value found. This could explain the discrepancy reported for the co-operativity value of the RecA-DNA interaction. The large cluster observed by electron microscopy indicates a very high co-operativity, whereas analysis of the binding isotherm indicates a moderate one, on the assumption of monomer. But if RecA is a large oligomer, the latter analysis would give a much higher co-operativity value and the former a smaller one, and they would be in accordance. Our sedimentation and light-scattering experiments suggest an oligomerization of about 30-mer or more, and support this explanation.

Allosteric Regulation↗
PubMed1993

Deficient antigen processing of a protein quaternary structure can be overcome by receptor-mediated uptake.

Human chorionic gonadotropin (hCG) is a dimer of non-covalently associated alpha (hCG-alpha) and beta (hCG-beta) subunits. This molecule was used to study whether receptor-mediated uptake influences the presentation of a protein quaternary structure. Unprimed splenocytes and a B cell lymphoma were capable of presenting only the free (hCG-alpha) but not the combined (hCG) alpha subunit to hCG-alpha T cell hybridomas, while hCG-alpha-primed lymph node cells (LNC) responded to both hCG-alpha and hCG. As antigen (Ag)-specific antigen-presenting cells (APC) present in the hCG-alpha-primed LNC population may be potentially effective for presenting hCG, we investigated the role of specific Ag capture, through mIg and Fc gamma R, in the processing and presentation of hCG and hCG-alpha to HAG5, a T cell hybridoma directed against the immunodominant region (amino acids 61-81) of hCG-alpha. Results showed that only B cells bearing membrane immunoglobulin capable of recognizing hCG-alpha and hCG, and present in hCG-alpha-primed mice, were extremely effective in presenting the free as well as the combined alpha subunit. The effect of FcR-mediated uptake was analyzed using a B cell line transfected with the Fc gamma RII-B2 gene to present immune complexes of either hCG-alpha or hCG. We found that hCG-alpha and hCG were presented equally well, whatever the Ag-binding site of each antibody to hCG or its alpha subunit. Using HBG 6, an hCG-beta T cell hybridoma, we performed similar experiments with the Fc gamma RII-B2 cell line and determined that the potentiation of hCG presentation to HBG 6 was similar to that observed with HAG 5. Then kinetic experiments were performed to examine the effect of Ag uptake through FcR on processing. Results demonstrated that the uptake pathway drastically influenced the expression of alpha T cell determinants in the alpha/beta dimer. In addition, treatment with cycloheximide, a protein synthesis inhibitor, only impaired the ability of APC to present specifically captured Ag. Thus, the processing pathway for specifically captured Ag might be different from the pathway used to process nonspecifically captured Ag. This observation might explain why receptor-enhanced uptake bypasses the inefficient processing of the hCG quaternary structure and enables similar efficiency in the presentation of alpha and beta T cell specificities. These findings provide new insight into the antigenicity of oligomeric molecules, which is modified whether antigen capture is specific or not.

Animals↗
PubMed1993

Influence of protein-quaternary structure on antigen processing.

T cell recognition of the quaternary structure of human chorionic gonadotropin (hCG), resulting from the association between its alpha (hCG-alpha) and beta (hCG-beta) subunits, was analyzed using hCG-alpha and hCG-beta T cell hybridomas produced in BALB/c mice. First, the fine specificity of these T cell hybridomas was determined, enabling us to divide hCG-alpha-specific T cell hybridomas into two groups. Group I recognized the hCG-alpha(61-81) region, and group II responded to the hCG-alpha(50-70) part of the molecule. Two groups of hCG-beta-specific T cell hybridomas, designated groups III and IV, were analyzed and found to respond to the C- and the N-terminal parts of the hCG-beta(1-22) peptide, respectively. Moreover, we observed that the nature of APC influenced Ag recognition by hCG-beta T cell hybridomas from group IV, but not by other selected T cell hybridomas. We then showed that recognition of the hCG alpha/beta dimer by alpha-specific T cell hybridomas was dramatically reduced compared to both free hCG-alpha and heat-dissociated hCG alpha/beta molecules. In contrast, hCG-beta hybridomas exhibited comparable responses to the free beta subunit and the hCG dimer. Experiments using a dimeric molecule assembled from the alpha-subunit of human follicle-stimulating hormone, which is identical to hCG-alpha, and the beta-subunit of human follicle-stimulating hormone, which is homologous to hCG-beta, confirmed that the three-dimensional structure of the complex rather than the primary structure of the beta-subunit plays a critical role in the processing pathway. Finally, kinetic experiments showed that the presentation of hCG-alpha T cell epitopes differed depending upon whether the alpha-subunit was in its free or combined form. In contrast, the kinetic expression of hCG-beta T cell epitopes appeared to be independent of the quaternary structure of hCG. Thus, conformational alterations resulting from the alpha/beta subunit association mainly influenced processing of the alpha-subunit in its complexed form, rather than processing of the combined beta-subunit. The effect of protein-quaternary structure on T cell recognition may represent a new element in our understanding of the processing and presentation of oligomeric molecules.

Animals↗
PubMed2005

Contribution of electrostatic interactions, compactness and quaternary structure to protein thermostability: lessons from structural genomics of Thermotoga maritima.

Studies of the structural basis of protein thermostability have produced a confusing picture. Small sets of proteins have been analyzed from a variety of thermophilic species, suggesting different structural features as responsible for protein thermostability. Taking advantage of the recent advances in structural genomics, we have compiled a relatively large protein structure dataset, which was constructed very carefully and selectively; that is, the dataset contains only experimentally determined structures of proteins from one specific organism, the hyperthermophilic bacterium Thermotoga maritima, and those of close homologs from mesophilic bacteria. In contrast to the conclusions of previous studies, our analyses show that oligomerization order, hydrogen bonds, and secondary structure play minor roles in adaptation to hyperthermophily in bacteria. On the other hand, the data exhibit very significant increases in the density of salt-bridges and in compactness for proteins from T.maritima. The latter effect can be measured by contact order or solvent accessibility, and network analysis shows a specific increase in highly connected residues in this thermophile. These features account for changes in 96% of the protein pairs studied. Our results provide a clear picture of protein thermostability in one species, and a framework for future studies of thermal adaptation.

Bacterial Proteins↗
PubMedDate not supplied

[Role of surface distribution of hydrophobic groups in the assembly of protein quaternary structure].

The method for two-dimensional representation of protein surfaces, based on the analogy with geographic map, and the algorithm for the search of the most favourable regions of izologous intermolecular interactions are proposed. It is assumed that the most favourable izologous interaction corresponds to an izologous contact of subunits which maximally dehydrates surface hydrophobic groups. The subunits are approximated by ellipsoids of revolution. The hydrophobic groups are assumed to be dehydrated if their C beta-atoms are inside the surface regions of the contacting ellipsoids inaccessible for contact with the sphere representing a water molecule. Using the proposed methods it is shown that for all izologous structures, known to atomic resolution, general shape of the molecule and distribution of hydrophobic groups on its surface: 1) provide a rough intersubunit recognition during assembly (deviation of the center of the experimentally localized contact region from the center of one of two-three regions obtained by us does not exceed 6--7 A); 2) choose only a few most favourable mutual orientations of the contacting regions; 3) can determine the pathway of the assembly.

Macromolecular Substances↗
PubMed1992

Membrane fusion process of Semliki Forest virus. I: Low pH-induced rearrangement in spike protein quaternary structure precedes virus penetration into cells.

The Semliki Forest virus (SFV) directs the synthesis of a heterodimeric membrane protein complex which is used for virus membrane assembly during budding at the surface of the infected cell, as well as for low pH-induced membrane fusion in the endosomes when particles enter new host cells. Existing evidence suggests that the E1 protein subunit carries the fusion potential of the heterodimer, whereas the E2 subunit, or its intracellular precursor p62, is required for binding to the nucleocapsid. We show here that during virus uptake into acidic endosomes the original E2E1 heterodimer is destabilized and the E1 proteins form new oligomers, presumably homooligomers, with altered E1 structure. This altered structure of E1 is specifically recognized by a monoclonal antibody which can also inhibit penetration of SFV into host cells as well as SFV-mediated cell-cell fusion, thus suggesting that the altered E1 structure is important for the membrane fusion. These results give further support for a membrane protein oligomerization-mediated control mechanism for the membrane fusion potential in alphaviruses.

Animals↗
PubMed2007

SNAPPI-DB: a database and API of Structures, iNterfaces and Alignments for Protein-Protein Interactions.

SNAPPI-DB, a high performance database of Structures, iNterfaces and Alignments of Protein-Protein Interactions, and its associated Java Application Programming Interface (API) is described. SNAPPI-DB contains structural data, down to the level of atom co-ordinates, for each structure in the Protein Data Bank (PDB) together with associated data including SCOP, CATH, Pfam, SWISSPROT, InterPro, GO terms, Protein Quaternary Structures (PQS) and secondary structure information. Domain-domain interactions are stored for multiple domain definitions and are classified by their Superfamily/Family pair and interaction interface. Each set of classified domain-domain interactions has an associated multiple structure alignment for each partner. The API facilitates data access via PDB entries, domains and domain-domain interactions. Rapid development, fast database access and the ability to perform advanced queries without the requirement for complex SQL statements are provided via an object oriented database and the Java Data Objects (JDO) API. SNAPPI-DB contains many features which are not available in other databases of structural protein-protein interactions. It has been applied in three studies on the properties of protein-protein interactions and is currently being employed to train a protein-protein interaction predictor and a functional residue predictor. The database, API and manual are available for download at: http://www.compbio.dundee.ac.uk/SNAPPI/downloads.jsp.

Cluster Analysis↗