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PubMed1997

Analysis of sequence patterns surrounding the translation initiation sites on Cyanobacterium genome using the hidden Markov model.

Sequence patterns surrounding the translation initiation sites of Cyanobacterium were precisely analyzed by the hidden Markov model (HMM) based on the actual translation initiation sites. In a previous study, 72 actual protein coding regions and their translation initiation sites on the genome of Synechocystis sp. strain PCC6803 were determined by Sazuka et al. using protein two-dimensional electrophoresis and microsequening. In this work, we extracted the sequence patterns surrounding translation initiation sites as HMM using the computer program YEBIS. The constructed HMM could recognize all but one translation initiation site. The HMM contains an AG-rich region (5.7 bp on average), as the Shine-Dalgarno sequence exclusively contains purines, upstream of the translation initiation site (-9.7 position on average) and a CT rich region (4.2 bp on average) just upstream from the translation initiation site. In addition, we found that the second amino acid (-4.5,6) could be classified into two types, one of which had C as their second codon while another of which has a nucleotide distribution relatively similar to the distribution among amino acids in the 72 proteins. This fact corresponds well to our earlier finding that when the second nucleotide of the second amino acid of a translated protein was C, an initial methionine was processed and that otherwise the methionine was intact with high frequency.

Base Sequence↗
PubMed2005

Age-related decline in actomyosin function.

To understand the molecular basis of the functional decline in aging muscle, we examined the functional (actomyosin ATPase) and chemical (cysteine content) changes in actin and myosin purified from the muscles of young (4- to 12-month-old) and old (27- to 35-month-old) Fisher 344 rats. Using the soluble, catalytically active myosin fragment, heavy meromyosin (HMM), we determined the maximum rate (V(max)) and actin concentration at half V(max) (K(m)) of the actomyosin ATPase, using four combinations of actin and HMM from old and young rats. V(max) and K(m) were significantly lower when both actin and HMM were obtained from old rats than when both proteins were obtained from young rats. The number of reactive cysteines in HMM significantly decreased with age, but no change was detected in the number of reactive cysteines in actin. We conclude that aging results in chemical changes in myosin (probably oxidation of cysteines) that have inhibitory effects on the actin-activated myosin ATPase.

Actins↗
PubMed1994

A hidden Markov model that finds genes in E. coli DNA.

A hidden Markov model (HMM) has been developed to find protein coding genes in E. coli DNA using E. coli genome DNA sequence from the EcoSeq6 database maintained by Kenn Rudd. This HMM includes states that model the codons and their frequencies in E. coli genes, as well as the patterns found in the intergenic region, including repetitive extragenic palindromic sequences and the Shine-Delgarno motif. To account for potential sequencing errors and or frameshifts in raw genomic DNA sequence, it allows for the (very unlikely) possibility of insertions and deletions of individual nucleotides within a codon. The parameters of the HMM are estimated using approximately one million nucleotides of annotated DNA in EcoSeq6 and the model tested on a disjoint set of contigs containing about 325,000 nucleotides. The HMM finds the exact locations of about 80% of the known E. coli genes, and approximate locations for about 10%. It also finds several potentially new genes, and locates several places were insertion or deletion errors/and or frameshifts may be present in the contigs.

Algorithms↗
PubMed2001

Two new modes of smooth muscle myosin regulation by the interaction between the two regulatory light chains, and by the S2 domain.

Previous studies indicated that single-headed smooth muscle myosin and S1 (a single head fragment) are not regulated through phosphorylation of the regulatory light chain (RLC). To investigate the importance of the double-headedness of myosin and of the S2 region for the phosphorylation-dependent regulation, we made three types of recombinant mutant smooth muscle HMMs with one intact head and an N-terminally truncated head. The truncated head of Delta MD lacked the motor domain, that of Delta(MD+ELC) lacked the motor and essential light chain binding domains, and single-headed HMM had one intact head alone. The basal ATPase activities of the three mutants decreased as the KCl concentration became less than 0.1 M. Such a decrease was not observed for S1, which had no S2 region, suggesting that S2 is necessary for this myosin behavior. This activity decrease also disappeared when RLCs of Delta MD and Delta(MD+ELC), but that of single-headed HMM, were phosphorylated. When their RLCs were unphosphorylated, the three mutants exhibited similar actin-activated ATPase levels. However, when they were phosphorylated, the actin-activated ATPase activities of Delta MD and Delta(MD+ELC) increased to the S1 level, while that of single-headed HMM remained unchanged. Even in the phosphorylated state, the actin-activated ATPase activities of the three mutants and S1 were much lower than that of wild-type HMM. We propose that S2 has an inhibitory function that is canceled by an interaction between two phosphorylated RLCs. We also propose that a cooperative interaction between two motor domains is required for a higher level of actin activation.

Actins↗
PubMed1996

Maleimidobenzoyl actin: its biochemical properties and in vitro motility.

Muscle G-actin treated with the hetero-bifunctional cross-linking reagent m-maleimidobenzoyl-N-hydroxysuccinimide ester (MBS), denoted as MBS-G-actin, is not induced to polymerize into F-actin by salt and myosin subfragment 1 [Bettache, N., Bertrand, R., and Kassab, R. (1989) Proc. Natl. Acad. Sci. USA 86, 6028-6032]. However, the addition of salt and phalloidin together allowed MBS-G-actin to polymerize and the resulting polymer (P-MBS-G-actin) could activate the Mg2+ -ATPase of S-1 [Miki, M. and Hozumi, T. (1991) Biochemistry 30, 5625-5630]. When F-actin was treated with MBS (MBS-F-actin), unlike MBS-G-actin, intercross-links between monomers in F-actin occurred. The MBS-F-actin could activate the Mg2+ -ATPase of heavy meromyosin (HMM): its maximum turnover rate, Vmax, was almost the same as that of native F-actin, but the affinity of HMM for MBS-F-actin in the presence of ATP, Km, was about 3 times higher. Electron microscopy showed that both P-MBS-G-actin and MBS-F-actin had the double stranded structures of F-actin and formed the arrowhead structures when combined with HMM. By in vitro motility assay, the sliding velocities of P-MBS-G-actin and MBS-F-actin were found to be slightly slower than that of native F-actin. But the critical concentration of KCl, over which the sliding movement was not observed, for MBS-modified actins was considerably higher than for native F-actin. When MBS-modified actins were regulated by tropomyosin-troponin complex, they were less sensitive to the Ca2+ concentration for HMM ATPase activation and sliding movement. These results showed that the modification of some of the lysine residues in the actin molecule leads to change in the biochemical properties of F-actin.

Actins↗
PubMed1976

Separation of subfragment-1 of H-meromyosin into two equimolar fractions with and without formation of the reactive enzyme-phosphate-ADP complex.

H-Meromyosin (HMM) was digested with insoluble papain [EC 3.4.22.2]. Neither the size of the initial burst of Pi liberation (0.5 mole/mole of myosin head) nor the Mg2+-ATPase [EC 3.6.1.3] activity of HMM in the steady state was affected by this treatment. Acto-S-1 was obtained by mixing F-actin with HMM digested with insoluble papain (HMM-S-1). The size of the initial burst of Pi liberation of acto-S-1 was 0.35 mole/mole of S-l at an ATP concentration of 0.5 mole/mole of S-1, and 0.5 mole/moleof S-1 at ATP concentrations above 1 mole/mole of S-1...

Actins↗
PubMed1976

Cooperative conformational change in F-actin filament induced by the binding of heavy meromyosin.

The binding of HMM to F-actin containing bound 1, N6-ethenoadenosine diphosphate (epsilon-ADP), a fluorescent analogue of ADP, caused a significant increase in the fluorescence intensity of epsilon-ADP at 410 nm on excitation at 340 nm. This increase is regarded as due to a conformational change in the actin molecule induced by HMM binding. The fluorescence intensity increase was not directly proportional to the amount of bound HMM. This phenomenon suggests that a conformational change in neighbouring actin molecules is induced cooperatively by the conformational change of the actin molecule binding HMM.

Actins↗
PubMed1981

Amphoteric charge distribution at the enzymatic site of 1,N6-ethenoadenosine triphosphate-binding heavy meromyosin determined by dynamic fluorescence quenching.

The features of the charge distribution in the vicinity of the ATP-binding site of heavy meromyosin (HMM) were investigated by the technique of dynamic fluorescence quenching. Instead of ATP, 1,N6-ethenoadenosine triphosphate (epsilon-ATP), a fluorescent derivative of ATP, was attached to the ATP-binding site in the presence of an ATP-regenerating system. The I- ion and acrylamide were used as negative- and zero-charged quenchers. In addition to these quenchers, we used the TI+ ion, which has recently been found to be a highly efficient quencher with positive charge, and to be generally applicable to fluorescence-labeled proteins. The Stern-Volmer quenching constants of TI+ and I- for epsilon-ATP bound to HMM both decreased with increasing ionic strength of the solvent. This result means that there is an electrostatic attractive force between the fluorophore ad both TI+ and I-. On the other hand, the Stern-Volmer quenching constant of acrylamide was not significantly affected by a change in ionic strength. This result confirms that no significant change in protein conformation in the vicinity of the epsilon-ATP-binding site of HMM occurs with change in ionic strength. In order to interpret these results, we propose a model in which a positive charge is located on one side of the epsilon-adenine ring and a negative charge is located on the opposite side. The negative charge is attributed to the phosphate group in epsilon-ATP and positive one is probably attributable to a lysyl residue in the polypeptide chain of HMM.

Adenosine Triphosphate↗
PubMed1981

N-terminal region of gizzard myosin heavy chain is critical for the ATPase activity.

Two different HMM species of gizzard myosin were prepared under conditions such that the phosphorylation of light chain was fully maintained. They were different in the N-terminal structure of the heavy chain but not in the light chain composition. A significant decrease in the Mg2+-ATPase activity was observed in one class of HMM which was proteolytically cleaved intramolecularly at site 1, 5 K daltons from the masked N terminus. Another class of HMM without the cleavage at site 1 showed ATPase activity similar to that of myosin. The decrease in ATPase activity was not caused by denaturation since similar amounts of initial burst of Pi liberation were observed with both HMMs and myosin. Kinetic and substructure analyses of HMM revealed that the activity change depended solely on the cleavage at site 1. The N-terminal region of gizzard myosin heavy chain may thus have an important role in maintaining the active site structure.

Adenosine Triphosphatases↗
PubMed1985

Fluorescence properties and contraction characteristics of ANM (N-(1-anilinonaphthyl-4)maleimide)-labeled rabbit psoas muscle fibers.

Fluorescence spectra of ANM-labeled, glycerinated rabbit psoas muscle fibers were recorded in relaxed, contracted, and rigor states. SDS polyacrylamide gel electrophoresis of the ANM-labeled muscle fibers indicated that proteins labeled with ANM were myosin heavy chain, C protein, and actin. In a relaxed state in the presence of ATP, myosin heavy chain was mainly labeled. During the transition from rigor to the relaxed or contracted state, there was a blue shift (about 5 nm) of the ANM emission spectrum. Similar experiments with FAM (N-(3-fluoranthyl)-maleimide)-labeled muscle fibers showed that these fluorescence changes were not artifacts due to the movement of muscle fibers. The fibers labeled in the ATP relaxing solution showed a marked decrease in both isometric force and unloaded shortening velocity (Vo), while in the fibers labeled in the rigor solution isometric tension was not markedly suppressed, though Vo decreased to the same extent as in the fibers labeled in the ATP relaxing solution. Fluorescence spectra of ANM-labeled HMM in different states were also measured. A fluorescence enhancement and a blue shift (about 5 nm) of the emission maximum were observed in HMM + MgATP or HMM + MgATP + F-actin in comparison with HMM + F-actin. These results suggest that the fluorescence spectra of the ANM-labeled muscle fibers reflect their conformational changes between the rigor state (in the absence of MgATP) and the relaxed or contracted state (in the presence of MgATP).

Actomyosin↗
PubMed1990

The role of hexamethylmelamine in the combination chemotherapy of advanced ovarian cancer: a comparison of hexamethylmelamine, cyclophosphamide, doxorubicin, and cisplatin (H-CAP) versus cyclophosphamide, doxorubicin, and cisplatin (CAP).

To evaluate the contribution of hexamethylmelamine (HMM) to the treatment of advanced ovarian cancer with combination chemotherapy, we compared the results of treatment with HMM, cyclophosphamide, doxorubicin, and cisplatin (H-CAP regimen) to treatment results using cyclophosphamide, doxorubicin, and cisplatin (CAP regimen). The treatment regimens were identical in dosage and schedule with the exception of the addition of HMM to one regimen. Fifty-five patients treated with H-CAP at Vanderbilt University Hospital between August 1977 and March 1980 were compared with a subsequent group of 22 patients who received CAP between October 1984 and October 1987. Following six months of therapy, patients were restaged either with second-look laparotomy or with clinical restaging. Fifty-three of 55 patients (96%) had objective responses to H-CAP compared with 14 of 21 patients (67%) treated with CAP (p = 0.001). The pathologic complete response rate was also higher in the patients who received H-CAP (35% versus 19%). The median survival of patients receiving H-CAP is 47 months compared to 21 months for the CAP patients. When patients with limited residual disease (maximum tumor diameter less than or equal to 3 cm) were compared, the median survival also favored the H-CAP treatment (101 months versus 21 months, p = 0.002). The median time to progression was also greater in patients receiving H-CAP versus those receiving CAP (67 months versus 16 months, p = 0.045). Treatment-related toxicity did not differ substantially between the two regimens. Our findings suggest that the addition of HMM to CAP chemotherapy prolongs the median survival in patients with ovarian cancer and limited residual disease following cytoreductive surgery.

Adult↗
PubMed2002

The structure and properties of gluten: an elastic protein from wheat grain.

The wheat gluten proteins correspond to the major storage proteins that are deposited in the starchy endosperm cells of the developing grain. These form a continuous proteinaceous matrix in the cells of the mature dry grain and are brought together to form a continuous viscoelastic network when flour is mixed with water to form dough. These viscoelastic properties underpin the utilization of wheat to give bread and other processed foods. One group of gluten proteins, the HMM subunits of glutenin, is particularly important in conferring high levels of elasticity (i.e. dough strength). These proteins are present in HMM polymers that are stabilized by disulphide bonds and are considered to form the 'elastic backbone' of gluten. However, the glutamine-rich repetitive sequences that comprise the central parts of the HMM subunits also form extensive arrays of interchain hydrogen bonds that may contribute to the elastic properties via a 'loop and train' mechanism. Genetic engineering can be used to manipulate the amount and composition of the HMM subunits, leading to either increased dough strength or to more drastic changes in gluten structure and properties.

Amino Acid Sequence↗
PubMed1998

Insertion mutagenesis of XpsD, an outer-membrane protein involved in extracellular protein secretion in Xanthomonas campestris pv. campestris.

XpsD is an outer-membrane protein required for extracellular protein secretion in Xanthomonas campestris pv. campestris. Cross-linking and gelfiltration chromatography analyses have suggested that it forms a multimer. To determine its structure-function relationship, linker-insertion mutants were constructed in an xpsD gene carried on a plasmid. To assay for secretion function, each mutant gene was introduced into an xpsD::Tn5 mutant strain (XC1708) and assayed for alpha-amylase secretion on starch plates. To test whether the mutant genes exerted a dominant-negative effect, each was introduced into the parental strain XC1701 and examined for secretion interference. Nine functional, one semi-functional and eleven non-functional mutants were obtained. All the non-functional mutants, except two for which the mutant proteins were undetectable on immunoblots, showed interference of normal secretion. The insertion sites in the different mutant proteins are randomly distributed throughout the entire sequence of the XpsD protein. All the permissive insertion sites are located where beta-turn or coiled secondary structure is predicted. Over half of the non-permissive sites are located within predicted helical or beta-sheet regions. By pretreating total membranes of XC1701 in SDS at 50 degrees C, an immunoreactive band with high molecular mass (HMM) could be detected that remained in the stacking gel during SDS-PAGE. The semi-functional and all functional mutant proteins formed HMM complexes that were as SDS-resistant as those of the wild-type, whereas all except three of the non-functional mutant proteins formed HMM structures that were less resistant to SDS than the wild-type. By analysing the appearance of SDS-resistant HMM complexes, we were able to detect conformational alterations in XpsD that are too subtle to be detected by other assays.

Amino Acid Sequence↗
PubMed2005

Continuous myoelectric control for powered prostheses using hidden Markov models.

This paper represents an ongoing investigation of dexterous and natural control of upper extremity prostheses using the myoelectric signal. The scheme described within uses a hidden Markov model (HMM) to process four channels of myoelectric signal, with the task of discriminating six classes of limb movement. The HMM-based approach is shown to be capable of higher classification accuracy than previous methods based upon multilayer perceptrons. The method does not require segmentation of the myoelectric signal data, allowing a continuous stream of class decisions to be delivered to a prosthetic device. Due to the fact that the classifier learns the muscle activation patterns for each desired class for each individual, a natural control actuation results. The continuous decision stream allows complex sequences of manipulation involving multiple joints to be performed without interruption. The computational complexity of the HMM in its operational mode is low, making it suitable for a real-time implementation. The low computational overhead associated with training the HMM also enables the possibility of adaptive classifier training while in use.

Action Potentials↗
PubMed2004

Identification of humans using gait.

We propose a view-based approach to recognize humans from their gait. Two different image features have been considered: the width of the outer contour of the binarized silhouette of the walking person and the entire binary silhouette itself. To obtain the observation vector from the image features, we employ two different methods. In the first method, referred to as the indirect approach, the high-dimensional image feature is transformed to a lower dimensional space by generating what we call the frame to exemplar (FED) distance. The FED vector captures both structural and dynamic traits of each individual. For compact and effective gait representation and recognition, the gait information in the FED vector sequences is captured in a hidden Markov model (HMM). In the second method, referred to as the direct approach, we work with the feature vector directly (as opposed to computing the FED) and train an HMM. We estimate the HMM parameters (specifically the observation probability B) based on the distance between the exemplars and the image features. In this way, we avoid learning high-dimensional probability density functions. The statistical nature of the HMM lends overall robustness to representation and recognition. The performance of the methods is illustrated using several databases.

Algorithms↗
PubMed1985

Absorption and metabolism of hexamethylmelamine and pentamethylmelamine in rat everted perfused gut segments: correlation with in-vivo data.

The intestinal oxidative metabolism of hexamethylmelamine (HMM) and pentamethylmelamine (PMM) has been studied in microsomes, isolated mucosal cells and intestinal perfused segments. (sub) Cellular systems revealed an almost equal Km (53-65 microM) and Vmax (5.6-7.0 nmol min-1 g-1 intestine) for both compounds. Detailed studies in everted intestinal perfused segments, showed that HMM is metabolized to a far greater extent than PMM (e.g. 11-times, at 80 microM substrate concentration) while PMM transport was 3 times greater than the transport of unchanged HMM. Only when perfused segments were used as an in-vitro tool was a good correlation observed between the in-vivo and in-vitro rate of intestinal metabolism of HMM and PMM. It is concluded that this is due to preservation of structural integrity of the mucosa for both absorptive and metabolic processes.

Altretamine↗
PubMed2003

Suppression of cytochrome P450 3A protein levels by proteasome inhibitors.

We have previously reported that CYP3A cross-links with polyubiquitinated proteins in microsomes from nicardipine-treated rats in a process that is distinct from classical polyubiquitination. To further examine the role of the proteasome in CYP3A degradation, we investigated the effects of proteasome inhibitors lactacystin, MG132, proteasome inhibitor 1, and hemin in primary cultures of rat and human hepatocytes. With the exception of hemin, these agents increased the total pool of ubiquitinated proteins in microsomes isolated from rat hepatocytes, indicating that lactacystin, MG132, and proteasome inhibitor 1 effectively inhibited the proteasome in these cells. All four agents caused a reduction in the amount of the major approximately 55-kDa CYP3A band, opposite to what would be expected if the ubiquitin-proteasome pathway degraded CYP3A. Only hemin treatment caused an increase in high molecular mass (HMM) CYP3A bands. Because hemin treatment did not alter levels of ubiquitin in CYP3A immunoprecipitates, the HMM CYP3A bands formed in response to hemin treatment clearly were not due to proteasome inhibition. Rather, because hemin treatment also caused an increase in HMM CYP3A in the detergent-insoluble fraction of the 10,000g pellet, the HMM CYP3A seems to represent a large protein complex that is unlikely to primarily represent ubiquitination.

Animals↗
PubMed1987

Disruption of the Dictyostelium myosin heavy chain gene by homologous recombination.

The phenomenon of homologous recombination, which allows specific gene conversion and gene insertion, can be a powerful system for the study of eukaryotic cell biology. Data are presented demonstrating that integration of a transfected plasmid by homologous recombination occurs in the motile eukaryotic cell Dictyostelium discoideum. A plasmid carrying a G418 resistance gene and the amino terminal half of the myosin heavy chain gene was used to transfect Dictyostelium. A large fraction of the resultant G418-resistant cells had the plasmid integrated into the single genomic copy of the heavy chain gene. These cells, which fail to express the native myosin but express the myosin fragment, are defective in cytokinesis and become large and multinucleate. In spite of the absence of native myosin, these cells, termed hmm cells, exhibit many forms of cell movement, including membrane ruffling, phagocytosis, and chemotaxis. The hmm cells can aggregate but are blocked at a later stage in the Dictyostelium developmental cycle. The hmm cells revert to the wild-type phenotype. Reversion of the hmm phenotype is due to excision and loss of the transforming plasmid. The revertant cells express native myosin, are G418 sensitive, and have a normal developmental cycle. These results constitute genetic proof that the intact myosin molecule is required for cytokinesis and not for karyokinesis.

Cell Division↗