Biomedical subjects

Jie Liang

Publications and source records attributed to Jie Liang.

At least 55 records · Page 3Linked to original sources

PubMed2004

Are residues in a protein folding nucleus evolutionarily conserved?

Protein is the working molecule of the cell, and evolution is the hallmark of life. It is important to understand how protein folding and evolution influence each other. Several studies correlating experimental measurement of residue participation in folding nucleus and sequence conservation have reached different conclusions. These studies are based on assessment of sequence conservation at folding nucleus sites using entropy or relative entropy measurement derived from multiple sequence alignment. Here we report analysis of conservation of folding nucleus using an evolutionary model alternative to entropy-based approaches. We employ a continuous time Markov model of codon substitution to distinguish mutation fixed by evolution and mutation fixed by chance. This model takes into account bias in codon frequency, bias-favoring transition over transversion, as well as explicit phylogenetic information. We measure selection pressure using the ratio omega of synonymous versus non-synonymous substitution at individual residue site. The omega-values are estimated using the PAML method, a maximum-likelihood estimator. Our results show that there is little correlation between the extent of kinetic participation in protein folding nucleus as measured by experimental phi-value and selection pressure as measured by omega-value. In addition, two randomization tests failed to show that folding nucleus residues are significantly more conserved than the whole protein, or the median omega value of all residues in the protein. These results suggest that at the level of codon substitution, there is no indication that folding nucleus residues are significantly more conserved than other residues. We further reconstruct candidate ancestral residues of the folding nucleus and suggest possible test tube mutation studies for testing folding behavior of ancient folding nucleus.

Amino Acid Sequence↗

PubMed2004

topoSNP: a topographic database of non-synonymous single nucleotide polymorphisms with and without known disease association.

The database of topographic mapping of Single Nucleotide Polymorphism (topoSNP) provides an online resource for analyzing non-synonymous SNPs (nsSNPs) that can be mapped onto known 3D structures of proteins. These include disease- associated nsSNPs derived from the Online Mendelian Inheritance in Man (OMIM) database and other nsSNPs derived from dbSNP, a resource at the National Center for Biotechnology Information that catalogs SNPs. TopoSNP further classifies each nsSNP site into three categories based on their geometric location: those located in a surface pocket or an interior void of the protein, those on a convex region or a shallow depressed region, and those that are completely buried in the interior of the protein structure. These unique geometric descriptions provide more detailed mapping of nsSNPs to protein structures. The current release also includes relative entropy of SNPs calculated from multiple sequence alignment as obtained from the Pfam database (a database of protein families and conserved protein motifs) as well as manually adjusted multiple alignments obtained from ClustalW. These structural and conservational data can be useful for studying whether nsSNPs in coding regions are likely to lead to phenotypic changes. TopoSNP includes an interactive structural visualization web interface, as well as downloadable batch data. The database will be updated at regular intervals and can be accessed at: http://gila.bioengr.uic.edu/snp/toposnp.

Computational Biology↗

PubMed2004

Evidence for separate tonal and segmental tiers in the lexical specification of words: a case study of a brain-damaged Chinese speaker.

We present an acoustic study of segmental and prosodic properties of words produced by a female speaker of Chinese with left-hemisphere brain damage. We measured the location of the point vowels /a, e, [Symbol: see text], i, y, o, u/ and determined their separation in the vowel plane, and their perceptual distinctivity. Similarly, the acoustic properties of the four lexical tones were measured in the F0 x time space. The data for our brain-damaged speaker were compared with those of a healthy control speaker. Results show that the patient's vowels hardly suffered from her lesion (relative to the vowel dispersion in the healthy control speaker), but that the identifiability of the four lexical tones was greatly compromised. These findings show that the tonal errors in aphasic speech behave independently of the segmental errors, even though both serve to maintain lexical contrasts in Chinese, and are therefore part of the lexical specification of Chinese words. The present study suggests that the specification of segmental and tonal aspects of lexical entries in Chinese, and in tone languages in general, are located or processed separately in the brain.

Adult↗

PubMed2004

The DNA architectural protein HMGB1 facilitates RTA-mediated viral gene expression in gamma-2 herpesviruses.

Replication and transcription activator (RTA), an immediate-early gene product of gamma-2 herpesviruses including Kaposi's sarcoma-associated herpesvirus (KSHV) and murine gamma herpesvirus 68 (MHV-68), plays a critical role in controlling the viral life cycle. RTA acts as a strong transcription activator for several downstream genes of KSHV and MHV-68 through direct DNA binding, as well as via indirect mechanisms. HMGB1 (also called HMG-1) protein is a highly conserved nonhistone chromatin protein with the ability to bind and bend DNA. HMGB1 protein promoted RTA binding to different RTA target sites in vitro, with greater enhancement to low-affinity sites than to high-affinity sites. Box A or box B and homologues of HMGB1 also enhanced RTA binding to DNA. Transient transfection of HMGB1 stimulated RTA transactivation of RTA-responsive promoters from KSHV and MHV-68. Furthermore, MHV-68 viral gene expression, as well as viral replication, was significantly reduced in HMGB1-deficient cells than in the wild type. This abated viral gene expression was partially restored by HMGB1 transfection into HMGB1(-/-) cells. These results suggest an important function of the DNA architectural protein, HMGB1, in RTA-mediated gene expression, as well as viral replication in gamma-2 herpesviruses.

Animals↗

PubMed2004

[The TGF-alpha gene Taq I polymorphism and non-syndromic cleft lip with or without cleft palate].

OBJECTIVE: To study the association of TGF-alpha gene Taq I polymorphism and nonsyndromic cleft lip with or without cleft palate (NSCL/P) in Chinese. METHODS: 107 patients with NSCL/P and 136 healthy controls were examined for TGF-alpha/Taq I genotypes. TGF-alpha/Taq I typing was carried out by digesting the locus specific polymerase chain reaction amplified products with alleles specific Taq I restriction enzyme (PCR-RELP). RESULTS: The C2 allele frequency of TGF-alpha/Taq I in patients with NSCL/P (16%) was significantly higher than that in healthy controls (8%). The C2 genotype frequency of TGF-alpha/Taq I in NSCL/P patients with positive family history (12.5%) was significantly higher than that in healthy controls. CONCLUSION: These findings demonstrate the role of TGF-alpha as a gene of major effects in the development of nonsyndromic cleft lip with or without cleft palate clefts in human. These findings suggest that a family history of clefting may correlate with the TGF-alpha Taq I rare variation.

Adolescent↗

PubMed2003

Simplicial edge representation of protein structures and alpha contact potential with confidence measure.

Protein representation and potential function are two important ingredients for studying protein folding, equilibrium thermodynamics, and sequence design. We introduce a novel geometric representation of protein contact interactions using the edge simplices from the alpha shape of the protein structure. This representation can eliminate implausible neighbors that are not in physical contact, and can avoid spurious contact between two residues when a third residue is between them. We developed statistical alpha contact potential using an odds-ratio model. A studentized bootstrap method was then introduced to assess the 95% confidence intervals for each of the 210 propensity parameters. We found, with confidence, that there is significant long-range propensity (>30 residues apart) for hydrophobic interactions. We tested alpha contact potential for native structure discrimination using several sets of decoy structures, and found that it often performs comparably with atom-based potentials requiring many more parameters. We also show that accurate geometric representation is important, and that alpha contact potential has better performance than potential defined by cutoff distance between geometric centers of side chains. Hierarchical clustering of alpha contact potentials reveals natural grouping of residues. To explore the relationship between shape and physicochemical representations, we tested the minimum alphabet size necessary for native structure discrimination. We found that there is no significant difference in performance of discrimination when alphabet size varies from 7 to 20, if geometry is represented accurately by alpha simplicial edges. This result suggests that the geometry of packing plays an important role, but the specific residue types are often interchangeable.

Amino Acid Sequence↗

PubMed2003

Inferring functional relationships of proteins from local sequence and spatial surface patterns.

We describe a novel approach for inferring functional relationship of proteins by detecting sequence and spatial patterns of protein surfaces. Well-formed concave surface regions in the form of pockets and voids are examined to identify similarity relationship that might be directly related to protein function. We first exhaustively identify and measure analytically all 910,379 surface pockets and interior voids on 12,177 protein structures from the Protein Data Bank. The similarity of patterns of residues forming pockets and voids are then assessed in sequence, in spatial arrangement, and in orientational arrangement. Statistical significance in the form of E and p-values is then estimated for each of the three types of similarity measurements. Our method is fully automated without human intervention and can be used without input of query patterns. It does not assume any prior knowledge of functional residues of a protein, and can detect similarity based on surface patterns small and large. It also tolerates, to some extent, conformational flexibility of functional sites. We show with examples that this method can detect functional relationship with specificity for members of the same protein family and superfamily, as well as remotely related functional surfaces from proteins of different fold structures. We envision that this method can be used for discovering novel functional relationship of protein surfaces, for functional annotation of protein structures with unknown biological roles, and for further inquiries on evolutionary origins of structural elements important for protein function.

Amino Acid Sequence↗

PubMed2003

CASTp: Computed Atlas of Surface Topography of proteins.

Computed Atlas of Surface Topography of proteins (CASTp) provides an online resource for locating, delineating and measuring concave surface regions on three-dimensional structures of proteins. These include pockets located on protein surfaces and voids buried in the interior of proteins. The measurement includes the area and volume of pocket or void by solvent accessible surface model (Richards' surface) and by molecular surface model (Connolly's surface), all calculated analytically. CASTp can be used to study surface features and functional regions of proteins. CASTp includes a graphical user interface, flexible interactive visualization, as well as on-the-fly calculation for user uploaded structures. CASTp is updated daily and can be accessed at http://cast.engr.uic.edu.

Binding Sites↗

PubMed2003

[Application of diffusion-weighted and perfusion magnetic resonance imaging in definition of the ischemic penumbra in hyperacute cerebral infarction].

OBJECTIVE: To investigate the value of diffusion-weighted imaging (DWI) and perfusion imaging (PI) in definition of the ischemic penumbra in hyperacute cerebral infarction. METHODS: (1) Animal study: Fifty-five SD rats were randomly divided into 5 groups of 10 rats. Nylon monofilament was inserted into the left middle cerebral artery (MCA) and immediately pulled out in 10 rats as controls (sham operation group or group A). The MCA of 40 rats was occluded by nylon monofilament for 30 minutes (group B), 60 minutes (group C), 180 minutes (group D), and 360 minutes (group E). Then all rats were examined by T(1)WI, T(2)WI, DWI, and PI. Apparent diffusion coefficient (ADC), regional cerebral blood volume (rCBV), relative cerebral blood flow (rCBF) and mean transit time (MTT) topographical maps were archived by the Workstation (GE SUN ADW3.0). The relative values of ADC, rCBV, rCBF, and MTT (ratios between the values of the occluded side and the opposite side) were calculated. The rats were killed and the cerebral infarction areas were stained by TTC (C(19)H(15)N(4)CI) and observed by light microscopy and electron microscopy. The results of microscopic examination were compared with the DWI results. (2) Clinical study: Forty-three patients, 24 males and 19 females,aged 68 years on average with acute stroke symptoms underwent MRI examination within 6 hours of symptom onset. T(1)WI, T(2)WI, DWI and PI were performed on all patients at the first MRI examination and T(2)WI was performed for follow up. The relevant parameters, including ADC, rCBV, rCBF and MTT were computed. The values of ADC, rCBV, rCBF and MTT within the lesions were compared to those at the normal sides and the ratio was calculated. The lesion volumes were measured in ADC map (as vDWI), MTT map (as vPI) and follow-up T(2)WI (as vCI). The differences between vDWI and vPI, and between vDWI and vCI were compared. RESULTS: (1) Animal study: In the control group DWI and PI showed no change in the signal intensity and no pathological change was found. Hyper-intensity signal was found in the T(2)WI in groups D and E. No abnormal signal was found in the T(1)WI in all groups. Abnormal signals were found in the MCA-supplying region in the DWI and PI of groups B, C, D, and E. The size of hyper-intensity signal in DWI along with the extension of occlusion time. TTC staining showed that the volume of unstained area was similar to that of hyper-intensity signal area in DWI image (t test, P > 0.05). PI showed a decrease of cerebral perfusion in the MCA-supplying region along with the extension of occlusion time. However, the size enlargement of occluded region was not as severe as shown by DWI along with the extension of occlusion time. The size of region with abnormal perfusion shown by PI was larger than that shown by DWI in groups B, C, and D. PI/DWI mismatch region, indicating the existence of ischemic penumbra zone, became gradually smaller along with the extension of occlusion time and almost disappeared 360 minutes after MCA occlusion. No significant change was found in the PI/DWI mismatch region by light microscope but slight swelling of mitochondrion and Golgi apparatus in neurons were observed by electron microscope. (2) Clinical study: The cases of 38 of the 43 patients were diagnosed as cerebral infarction by clinical and MRI follow-up examinations. The first MRI examination of these 38 cases showed no abnormal signal in T(1)WI and hyper-intensity signal in T(2)WI of 4 cases. The vPI was larger than vDWI in 31 cases and the vPI was equal to or smaller than the vDWI in 7 cases. Follow-up examination showed that vCI was larger than vDWI in 28 cases and vCI almost equaled to vDWI in 10 cases. Spearman correlation analysis showed a positive correlation between the volume of ischemic penumbra zone and that of infarction (r = 0.689, P < 0.001) which suggests that the volume change of ischemic penumbra zone influences the size of final infarction directly. CONCLUSION: Combination of DWI and PI clearly defines the ischemic penumbra in hyperacute stroke patient, thus laying, thus laying a basis for therapeutic intervention plan for stroke patients.

Acute Disease↗

PubMed2003

Position-dependence of stabilizing polar interactions of asparagine in transmembrane helical bundles.

Recent studies with model peptides and statistical analyses of the crystal structures of membrane proteins have shown that buried polar interactions contribute significantly to the stabilization of the three-dimensional structures of membrane proteins. Here, we probe how the location of these polar groups along the transmembrane helices affect their free energies of interaction. Asn residues were placed singly and in pairs at three positions within a model transmembrane helix, which had previously been shown to support the formation of trimers in micelles. The model helix was designed to form a transmembrane coiled coil, with Val side chains at the "a" positions of the heptad repeat. Variants of this peptide were prepared in which an Asn residue was introduced at one or more of the "a" positions, and their free energies of association were determined by analytical ultracentrifugation. When placed near the middle of the transmembrane helix, the formation of trimers was stabilized by at least -2.0 kcal/mol per Asn side chain. When the Asn was placed at the interface between the hydrophobic and polar regions of the peptide, the substitution was neither stabilizing nor destabilizing (0.0 +/- 0.5 kcal/mol of monomer). Finally, it has previously been shown that a Val-for-Asn mutation in a water-soluble coiled coil destabilizes the structure by approximately 1.5 kcal/mol of monomer [Acharya, A., et al. (2002) Biochemistry 41, 14122-14131]. Thus, the headgroup region of a micelle appears to have a conformational impact intermediate between that of bulk water and the apolar region of micelle. A similarly large dependence on the location of the polar residues was found in a statistical survey of helical transmembrane proteins. The tendency of different types of residues to be buried in the interiors versus being exposed to lipids was analyzed. Asn and Gln show a very strong tendency to be buried when they are located near the middle of a transmembrane helix. However, when placed near the ends of transmembrane helices, they show little preference for the surface versus the interior of the protein. These data show that Asn side chains within the apolar region of the transmembrane helix provide a significantly larger driving force for association than Asn residues near the apolar/polar interface. Thus, although polar interactions are able to strongly stabilize the folding of membrane proteins, the energetics of association depend on their location within the hydrophobic region of a transmembrane helix.

Amino Acid Sequence↗

PubMed2003

Structural location of disease-associated single-nucleotide polymorphisms.

Non-synonymous single-nucleotide polymorphism (nsSNP) of genes introduces amino acid changes to proteins, and plays an important role in providing genetic functional diversity. To understand the structural characteristics of disease-associated SNPs, we have mapped a set of nsSNPs derived from the online mendelian inheritance in man (OMIM) database to the structural surfaces of encoded proteins. These nsSNPs are disease-associated or have distinctive phenotypes. As a control dataset, we mapped a set of nsSNPs derived from SNP database dbSNP to the structural surfaces of those encoded proteins. Using the alpha shape method from computational geometry, we examine the geometric locations of the structural sites of these nsSNPs. We classify each nsSNP site into one of three categories of geometric locations: those in a pocket or a void (type P); those on a convex region or a shallow depressed region (type S); and those that are buried completely in the interior (type I). We find that the majority (88%) of disease-associated nsSNPs are located in voids or pockets, and they are infrequently observed in the interior of proteins (3.2% in the data set). We find that nsSNPs mapped from dbSNP are less likely to be located in pockets or voids (68%). We further introduce a novel application of hidden Markov models (HMM) for analyzing sequence homology of SNPs on various geometric sites. For SNPs on surface pocket or void, we find that there is no strong tendency for them to occur on conserved residues. For SNPs buried in the interior, we find that disease-associated mutations are more likely to be conserved. The approach of classifying nsSNPs with alpha shape and HMM developed in this study can be integrated with additional methods to improve the accuracy of predictions of whether a given nsSNP is likely to be disease-associated.

Disease↗

PubMed2003

Higher-order interhelical spatial interactions in membrane proteins.

Higher-order interactions are important for protein folding and assembly. We introduce the concept of interhelical three-body interactions as derived from Delaunay triangulation and alpha shapes of protein structures. In addition to glycophorin A, where triplets are strongly correlated with protein stability, we found that tight interhelical triplet interactions exist extensively in other membrane proteins, where many types of triplets occur far more frequently than in soluble proteins. We developed a probabilistic model for estimating the value of membrane helical interaction triplet (MHIT) propensity. Because the number of known structures of membrane proteins is limited, we developed a bootstrap method for determining the 95% confidence intervals of estimated MHIT values. We identified triplets that have high propensity for interhelical interactions and are unique to membrane proteins, e.g. AGF, AGG, GLL, GFF and others. A significant fraction (32%) of triplet types contains triplets that may be involved in interhelical hydrogen bond interactions, suggesting the prevalent and important roles of H-bond in the assembly of TM helices. There are several well-defined spatial conformations for triplet interactions on helices with similar parallel or antiparallel orientations and with similar right-handed or left-handed crossing angles. Often, they contain small residues and correspond to the regions of the closest contact between helices. Sequence motifs such as GG4 and AG4 can be part of the three-body interactions that have similar conformations, which in turn can be part of a higher-order cooperative four residue spatial motif observed in helical pairs from different proteins. In many cases, spatial motifs such as serine zipper and polar clamp are part of triplet interactions. On the basis of the analysis of the archaeal rhodopsin family of proteins, tightly packed triplet interactions can be achieved with several different choices of amino acid residues.

Amino Acid Motifs↗

PubMed2003

Interhelical hydrogen bonds in transmembrane region are important for function and stability of Ca2+-transporting ATPase.

Ca2+-transporting adenosine triphosphatase (ATPase) of sarcoplasmic reticulum couples ATP hydrolysis with ion transport. Phosphorylation of the cytosolic region of the calcium-bound conformation (E1) of the protein leads to drastic conformational rearrangements of the transmembrane helices and the release of Ca2+. The resulting calcium-free conformation (E2) is less stable than the E1 form. The changes in van der Waals interactions and interhelical hydrogen bonding in the E1 and E2 conformations were compared. Conformational changes in the transmembrane region concomitant with the release of Ca2+ mainly affect the number of interhelical hydrogen bonds, which is reduced to half of that in E1 form, whereas the number of interhelical atomic pairwise contacts reflecting van der Waals interactions experience little change. The interhelical hydrogen bonds in Ca2+-transporting ATPase can be divided into two groups according to their roles: those that play a structural stabilizing role and those that are important for the correct geometry of the Ca2+ binding site. Interhelical hydrogen bonds in the transmembrane regions play important roles for the stability and specificity of helix-helix interactions in proteins where change of conformation is required for transport of ions or small molecules.

Amino Acids↗

PubMed2003

Changes of plasma membrane ATPase activities and proline accumulation in twigs of Casuarina under different growth conditions.

Twigs of Casuarina were collected from Dongshan and Xiamen Island, China. Crude plasma membrane preparation was obtained from Casuarina twigs by ultra-centrifugation. Sealed plasma membrane vesicles were isolated with aqueous PEG3350-Dextran T500 two phase partitioning. We studied the proline accumulation in twigs and the ATPase activities of plasma membrane of Casurina under different growth conditions. The results showed that free proline content and the PM ATPase activities from unfavorable growth conditions were obviously higher than those from favorable environment. This suggested that Casuarina responded to osmotic stress by increasing osmotic material content and the proton transportation activities of PM ATPase.

Adenosine Triphosphatases↗

PubMed2003

[Study on the energy expenditure in college students in Guangdong Province].

UNLABELLED: To investigate the energy expenditure of college students, 61 college students (30 male and 31 female) in Guangdong were selected as the participants. Basal metabolism was measured by indirect calorimetry. The activities of college students were systematically recorded using 24 hours recall method. Total energy expenditure was evaluated by the factorial calculation method of WHO. RESULTS: Basal metabolism rates of male and female college students were (158.03 +/- 7.85) kJ/(m2.h) and (145.05 +/- 10.14) kJ/(m2.h) respectively. Total energy expenditure of 24 hours were (10389.23 +/- 1519.90) kJ/d and (7921.15 +/- 961.41) kJ/d respectively. CONCLUSION: The energy expenditure of college students in South-China accorded with the criteria of "Chinese adults at light physical activity level".

Adult↗

PubMed2002

Interhelical hydrogen bonds and spatial motifs in membrane proteins: polar clamps and serine zippers.

Polar and ionizable amino acid residues are frequently found in the transmembrane (TM) regions of membrane proteins. In this study, we show that they help to form extensive hydrogen bond connections between TM helices. We find that almost all TM helices have interhelical hydrogen bonding. In addition, we find that a pair of contacting TM helices is packed tighter when there are interhelical hydrogen bonds between them. We further describe several spatial motifs in the TM regions, including "Polar Clamp" and "Serine Zipper," where conserved Ser residues coincide with tightly packed locations in the TM region. With the examples of halorhodopsin, calcium-transporting ATPase, and bovine cytochrome c oxidase, we discuss the roles of hydrogen bonds in stabilizing helical bundles in polytopic membrane proteins and in protein functions.

Amino Acid Motifs↗

PubMed2002

Hydration effects of heparin on antithrombin probed by osmotic stress.

Antithrombin is a key inhibitor of blood coagulation proteases and a prototype metastable protein. Heparin binding to antithrombin induces conformational transitions distal to the binding site. We applied osmotic stress techniques and rate measurements in the stopped flow fluorometer to investigate the possibility that hydration changes are associated with these transitions. Water transfer was identified from changes in the free energy of activation, Delta G(++), with osmotic pressure pi. The Delta G(++) was determined from the rate of fluorescence enhancement/decrease associated with heparin binding/release. The volume of water transferred, Delta V, was determined from the relationship, Delta G/pi = Delta V. With an osmotic probe of 4 A radius, the volumes transferred correspond to 158 +/- 11 water molecules from reactants to bulk during association and 162 +/- 22 from bulk to reactants during dissociation. Analytical characterization of water-permeable volumes in x-ray-derived bound and free antithrombin structures were correlated with the volumes measured in solution. Volume changes in water permeable pockets were identified at the loop-insertion and heparin-binding regions. Analyses of the pockets' atomic composition indicate that residues Ser-79, Ala-86, Val-214, Leu-215, Asn-217, Ile-219, and Thr-218 contribute atoms to both the heparin-binding pockets and to the loop-insertion region. These results demonstrate that the increases and decreases in the intrinsic fluorescence of antithrombin during heparin binding and release are linked to dehydration and hydration reactions, respectively. Together with the structural analyses, results also suggest a direct mechanism linking heparin binding/release to loop expulsion/insertion.

Alanine↗

PubMed2002

Experimental and computational studies of determinants of membrane-protein folding.

Recent experiments and analysis have demonstrated the important roles of hydrogen bonding and polar-polar interactions in driving transmembrane helix-helix association. Further details of the energetics of helix-helix association and interhelical packing geometry are being mapped out. Many sequence motifs and a few spatial motifs promoting helical associations have also been identified.

Amino Acid Motifs↗