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the study of proteins in vivo is often concerned with the synthesis and localization of the protein within the cell although many intracellular proteins are synthesized in the cytoplasm and membrane @@ bound or secreted proteins in the endoplasmic reticulum the specifics of how proteins are targeted to specific organelles or cellular structures is often unclear a useful technique for assessing cellular localization uses genetic engineering to express in a cell a fusion protein or chimera consisting of the natural protein of interest linked to a reporter such as green fluorescent protein ( gfp ) the fused protein 's position within the cell can be cleanly and efficiently visualized using microscopy as shown in the figure opposite
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other methods for elucidating the cellular location of proteins requires the use of known compartmental markers for regions such as the er the golgi lysosomes or vacuoles mitochondria chloroplasts plasma membrane etc with the use of fluorescently tagged versions of these markers or of antibodies to known markers it becomes much simpler to identify the localization of a protein of interest for example indirect immunofluorescence will allow for fluorescence colocalization and demonstration of location fluorescent dyes are used to label cellular compartments for a similar purpose
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other possibilities exist as well for example immunohistochemistry usually utilizes an antibody to one or more proteins of interest that are conjugated to enzymes yielding either luminescent or <unk> signals that can be compared between samples allowing for localization information another applicable technique is <unk> in sucrose ( or other material ) gradients using <unk> centrifugation while this technique does not prove colocalization of a compartment of known density and the protein of interest it does increase the likelihood and is more amenable to large @@ scale studies
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finally the gold @@ standard method of cellular localization is <unk> microscopy this technique also uses an antibody to the protein of interest along with classical electron microscopy techniques the sample is prepared for normal electron microscopic examination and then treated with an antibody to the protein of interest that is conjugated to an extremely electro @@ dense material usually gold this allows for the localization of both ultrastructural details as well as the protein of interest
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through another genetic engineering application known as site @@ directed mutagenesis researchers can alter the protein sequence and hence its structure cellular localization and susceptibility to regulation this technique even allows the incorporation of unnatural amino acids into proteins using modified trnas and may allow the rational design of new proteins with novel properties
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= = = proteomics = = =
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the total complement of proteins present at a time in a cell or cell type is known as its proteome and the study of such large @@ scale data sets defines the field of proteomics named by analogy to the related field of genomics key experimental techniques in proteomics include 2d electrophoresis which allows the separation of a large number of proteins mass spectrometry which allows rapid high @@ throughput identification of proteins and sequencing of peptides ( most often after in @@ gel digestion ) protein microarrays which allow the detection of the relative levels of a large number of proteins present in a cell and two @@ hybrid screening which allows the systematic exploration of protein protein interactions the total complement of biologically possible such interactions is known as the interactome a systematic attempt to determine the structures of proteins representing every possible fold is known as structural genomics
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= = = bioinformatics = = =
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a vast array of computational methods have been developed to analyze the structure function and evolution of proteins
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the development of such tools has been driven by the large amount of genomic and proteomic data available for a variety of organisms including the human genome it is simply impossible to study all proteins experimentally hence only a few are subjected to laboratory experiments while computational tools are used to extrapolate to similar proteins such homologous proteins can be efficiently identified in distantly related organisms by sequence alignment genome and gene sequences can be searched by a variety of tools for certain properties sequence profiling tools can find restriction enzyme sites open reading frames in nucleotide sequences and predict secondary structures phylogenetic trees can be constructed and evolutionary hypotheses developed using special software like clustalw regarding the ancestry of modern organisms and the genes they express the field of bioinformatics is now indispensable for the analysis of genes and proteins
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= = = = structure prediction and simulation = = = =
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complementary to the field of structural genomics protein structure prediction seeks to develop efficient ways to provide plausible models for proteins whose structures have not yet been determined experimentally the most successful type of structure prediction known as homology modeling relies on the existence of a template structure with sequence similarity to the protein being modeled structural genomics ' goal is to provide sufficient representation in solved structures to model most of those that remain although producing accurate models remains a challenge when only distantly related template structures are available it has been suggested that sequence alignment is the bottleneck in this process as quite accurate models can be produced if a perfect sequence alignment is known many structure prediction methods have served to inform the emerging field of protein engineering in which novel protein folds have already been designed a more complex computational problem is the prediction of intermolecular interactions such as in molecular docking and protein protein interaction prediction
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the processes of protein folding and binding can be simulated using such technique as molecular mechanics in particular molecular dynamics and monte carlo which increasingly take advantage of parallel and distributed computing ( folding @ home project molecular modeling on gpu ) the folding of small α @@ helical protein domains such as the villin headpiece and the hiv accessory protein have been successfully simulated in silico and hybrid methods that combine standard molecular dynamics with quantum mechanics calculations have allowed exploration of the electronic states of rhodopsins
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= = = = protein disorder and <unk> prediction = = = =
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many proteins ( in <unk> ~ 33 ) contain large unstructured but biologically functional segments and can be classified as intrinsically disordered proteins predicting and analysing protein disorder is therefore an important part of protein structure characterisation
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= = nutrition = =
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most microorganisms and plants can biosynthesize all 20 standard amino acids while animals ( including humans ) must obtain some of the amino acids from the diet the amino acids that an organism cannot synthesize on its own are referred to as essential amino acids key enzymes that synthesize certain amino acids are not present in animals such as <unk> which catalyses the first step in the synthesis of lysine methionine and threonine from aspartate if amino acids are present in the environment microorganisms can conserve energy by taking up the amino acids from their surroundings and downregulating their biosynthetic pathways
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in animals amino acids are obtained through the consumption of foods containing protein ingested proteins are then broken down into amino acids through digestion which typically involves denaturation of the protein through exposure to acid and hydrolysis by enzymes called proteases some ingested amino acids are used for protein biosynthesis while others are converted to glucose through gluconeogenesis or fed into the citric acid cycle this use of protein as a fuel is particularly important under starvation conditions as it allows the body 's own proteins to be used to support life particularly those found in muscle amino acids are also an important dietary source of nitrogen
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= = history and etymology = =
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proteins were recognized as a distinct class of biological molecules in the eighteenth century by antoine fourcroy and others distinguished by the molecules ' ability to coagulate or <unk> under treatments with heat or acid noted examples at the time included albumin from egg whites blood serum albumin fibrin and wheat gluten
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proteins were first described by the dutch chemist gerardus johannes mulder and named by the swedish chemist jöns jacob berzelius in 1838 mulder carried out elemental analysis of common proteins and found that nearly all proteins had the same empirical formula <unk> he came to the erroneous conclusion that they might be composed of a single type of ( very large ) molecule the term protein to describe these molecules was proposed by mulder 's associate berzelius protein is derived from the greek word <unk> ( <unk> ) meaning primary in the lead or standing in front + in mulder went on to identify the products of protein degradation such as the amino acid leucine for which he found a ( nearly correct ) molecular weight of 131 da
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early nutritional scientists such as the german carl von voit believed that protein was the most important nutrient for maintaining the structure of the body because it was generally believed that flesh makes flesh karl heinrich <unk> extended known protein forms with the identification of glutamic acid at the connecticut agricultural experiment station a detailed review of the vegetable proteins was compiled by thomas burr osborne working with lafayette mendel and applying liebig 's law of the minimum in feeding laboratory rats the nutritionally essential amino acids were established the work was continued and communicated by william cumming rose the understanding of proteins as polypeptides came through the work of franz hofmeister and hermann emil fischer the central role of proteins as enzymes in living organisms was not fully appreciated until 1926 when james b sumner showed that the enzyme urease was in fact a protein
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the difficulty in purifying proteins in large quantities made them very difficult for early protein biochemists to study hence early studies focused on proteins that could be purified in large quantities eg those of blood egg white various toxins and digestive / metabolic enzymes obtained from slaughterhouses in the 1950s the armour hot dog co purified 1 kg of pure bovine pancreatic ribonuclease a and made it freely available to scientists this gesture helped ribonuclease a become a major target for biochemical study for the following decades
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linus pauling is credited with the successful prediction of regular protein secondary structures based on hydrogen bonding an idea first put forth by william astbury in 1933 later work by walter <unk> on denaturation based partly on previous studies by kaj linderstrøm @@ lang contributed an understanding of protein folding and structure mediated by hydrophobic interactions
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the first protein to be sequenced was insulin by frederick sanger in 1949 sanger correctly determined the amino acid sequence of insulin thus conclusively demonstrating that proteins consisted of linear polymers of amino acids rather than branched chains colloids or cyclols he won the nobel prize for this achievement in 1958
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the first protein structures to be solved were hemoglobin and myoglobin by max perutz and sir john cowdery kendrew respectively in 1958 as of 2016 the protein data bank has over 115 @@ 000 atomic @@ resolution structures of proteins in more recent times cryo @@ electron microscopy of large macromolecular assemblies and computational protein structure prediction of small protein domains are two methods approaching atomic resolution
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= = textbooks = =
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= = = databases and projects = = =
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the protein naming utility
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human protein atlas
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ncbi entrez protein database
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ncbi protein structure database
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human protein reference database
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human <unk>
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folding @ home ( stanford university )
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comparative <unk> database curates protein chemical interactions as well as gene / protein disease relationships and chemical @@ disease relationships
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bioinformatic harvester a meta search engine ( 29 databases ) for gene and protein information
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protein databank in europe ( see also <unk> short articles and tutorials on interesting pdb structures )
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research collaboratory for structural bioinformatics ( see also molecule of the month presenting short accounts on selected proteins from the pdb )
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proteopedia life in 3d rotatable zoomable 3d model with wiki annotations for every known protein molecular structure
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<unk> the universal protein resource
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<unk> exploring the universe of human proteins human @@ centric protein knowledge resource
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multi @@ <unk> profiling expression database <unk> human and model organism protein / gene knowledge and expression data
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= = = tutorials and educational websites = = =
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an introduction to proteins from <unk> ( huntington 's disease outreach project for education at stanford )
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proteins biogenesis to degradation the virtual library of biochemistry and cell biology
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alphabet of protein structures
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= lisa ( japanese musician born 1987 ) =
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risa oribe ( <unk> <unk> oribe risa born june 24 1987 ) better known by her stage name lisa ( an acronym of love is same all ) is a japanese pop singer @@ songwriter from seki gifu signed to aniplex under sony music artists after aspiring to become a musician early in life she started her musical career as the vocalist of the indie band chucky following chucky 's disbandment in 2005 lisa moved to tokyo in order to pursue a solo career making her major debut in 2010 singing songs for the anime television series angel beats as one of two vocalists for the fictional band girls dead monster in april 2011 she made her solo debut with the release of her mini @@ album letters to u she performed at animelo summer live in august 2010 anime expo in 2012 and is a regular guest at anime festival asia
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lisa 's songs have been featured as theme music for various anime such as fate / zero and sword art online her singles have regularly been in the top ten of the oricon weekly charts with crossing field being certified platinum by the recording industry association of japan and oath sign being certified gold she performed at the nippon budokan in 2014 and 2015 in 2015 she made her acting debut as madge nelson in the japanese dub of the animated film minions
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= = career = =
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= = = early years and major debut = = =
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oribe 's musical experience began at the age of three when upon her mother 's suggestions she took private piano lessons although she was a shy student in kindergarten she enjoyed her music lessons in primary school she was inspired to sing after seeing the band speed on television she later took dance and vocal lessons which continued through her junior high school years while in elementary she participated in an audition held at the nippon budokan and it was during this time she decided to become an artist in junior high school she formed a band which covered songs by avril lavigne love <unk> and ego @@ <unk> '
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oribe began her singing career in 2005 during her first year in high school when she formed the indie rock band chucky which mainly covered songs by other artists during her second year the band received advice from their peers that they should start making their own songs eventually the band 's reputation grew enough that they performed in osaka and nagoya in addition to gifu although her grades in high school were good she decided not to go to university despite the recommendations of her teachers in order to focus on her work with chucky nevertheless after graduation due to varying schedules among the band 's members it became difficult to continue performing following the band 's disbandment in july 2008 she moved to tokyo in order to continue her singing career
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after moving to tokyo oribe formed the band love is same all with members from the indie band parking out and began using the stage name lisa which is an acronym for love is same all the band performs with lisa during the latter 's solo live performances in 2010 she made her major debut singing songs for the anime series angel beats as one of two vocalists for the fictional in @@ story band girls dead monster she was the vocalist for the character yui and the second vocalist marina sang as the character masami iwasawa lisa put out three singles and one album in 2010 under the name girls dead monster on key 's record label key sounds label the first single thousand enemies was released on may 12 the second single little braver came out on june 9 and the third single ichiban no takaramono ( yui final ver ) ( <unk> 〜 yui final ver 〜 my most precious treasure ( yui final ver ) ) was sold on december 8 the album keep the beats was released on june 30 lisa made her first appearance at animelo summer live during the concert 's 2010 iteration on august 28
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lisa made her solo debut on april 20 2011 with the release of her mini @@ album letters to u by aniplex under sony music artists the songs on the album were composed by dōjin and major artists and she composed the first song believe in myself she wrote the album 's lyrics on november 12 2011 she made her first appearance in singapore at anime festival asia southeast asia 's largest anime and pop culture convention she released her first solo single oath sign on november 23 2011 which was used as the opening theme to the 2011 anime series fate / zero the single peaked at no 5 on the oricon weekly charts and was certified gold by the recording industry association of japan ( riaj )
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= = = 2012 present = = =
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lisa released her first full solo album lover s mile on february 22 2012 the album peaked at no 7 on the oricon weekly charts she attended the anime expo 2012 in los angeles as a guest of honor and performed her first concert in north america there on july 1 after her success with oath sign she was chosen to perform the first opening theme to the 2012 anime series sword art online the single crossing field her second single was released on august 8 2012 the single peaked at no 5 on oricon and was later certified gold by the riaj her third single best day best way which peaked at no 6 on oricon was released on april 3 2013 and her fourth single träumerei which peaked at no 15 on oricon and was used as the opening theme to the 2013 anime series day break illusion was released on august 7 2013 lisa released her second solo album landspace on october 30 2013 the album peaked at no 2 on oricon charts a photobook titled kyō mo ii hi da ( <unk> another great day ) that contains photos of her taken by lis ani magazine over three years was published on november 22 2013 when asked if she would revisit the meaning of her acronym in the future in an interview with <unk> at anime festival asia 2013 in singapore she suggested lovely international super apple
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on january 3 2014 lisa held a sold @@ out solo concert at the nippon budokan her fifth single rising hope which is used as the opening theme to the 2014 anime series the irregular at magic high school was released on may 7 2014 the single peaked at no 4 on oricon she later covered the songs headphone actor ( <unk> ) and <unk> yesterday ( <unk> yesterday evening ) from the <unk> project franchise for the sixth episode of the 2014 anime series <unk> actors she released her sixth single bright flight / l miranic on september 17 2014 which peaked at no 8 on oricon and her seventh single <unk> ( <unk> lit sign ) on december 10 2014 which peaked at no 3 on the oricon the title song is used as the third ending theme to the 2014 anime series sword art online ii and the single also includes the song no more time machine which was used as the second ending theme to sword art online ii she held her second nippon budokan concert on january 10 and 11 2015 tickets for which were sold out she released her third solo album launcher on march 4 2015 and her eighth single rally go round on may 27 2015 the song is used as the opening theme to the second season of the anime television series <unk> she was cast as madge nelson in the japanese dub of the animated film minions which premiered in japanese theaters on july 31 2015 she released her ninth single empty mermaid on september 30 2015 in late 2015 she performed id which is used as theme song of the 2015 video game dengeki bunko fighting climax ignition to commemorate her fifth year as a solo artist lisa released her letters to u ep as a limited edition lp on march 23 2016 lisa released a mini @@ album titled lucky hi five on april 20 2016 she will release the single brave freak out which will be used as the opening theme to the 2016 anime television series <unk> code on august 24 2016
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= = musical style and influences = =
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lisa lists avril lavigne oasis green day paramore ke $ ha and rihanna as among her musical influences as well as her time in chucky lisa wrote the lyrics for some of her songs in her landspace and launcher albums as well as the lyrics for the singles bright flight / l miranic <unk> and rally go round rally go round was co @@ written with songwriter shin furuya
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lisa 's musical style is described by dennis amith of j ent as a young woman with style beautiful vocals and the ability to take on various musical styles may it be happy upbeat rock music or even something more darker she has used the phrase kyō mo ii hi da ( <unk> another great day ) as a theme throughout her career the phrase is also the name of her personal blog in an interview with hmv japan she mentioned that before her major debut she tended to sing pop songs and because of this she felt uneasy when making oath sign which had a heavy and dark style although she was able to receive several favorable responses to the single which allowed her to make her next single crossing field with confidence as for crossing field she says that feels that the song grows every time she sings it in the same way that love is nurtured through dates or love letters in best day best way she mentioned that the song 's theme is what you did yesterday will lead to what happens today and that the lyrics are delivered as if they are her own words she also shared her experience with the single 's b @@ sides i 'm a rock star which according to her represents her fulfilling her dream of becoming a singer and shiroi <unk> ( <unk> white sigh ) which represents happy feelings
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in an interview with oricon lisa explained her experiences with träumerei where she stated that because day break illusion is an original anime she wanted the song to be presented in the color of her own work but even in the world of anime her music would continue to have an atmosphere of rock as opposed to the pop style she used in best day best way she mentioned that she sang that song in a way that she felt the conflicts that were present in the story and with the strength that was part of the show 's theme with regards to the song 's music video she wanted to have a video which would express in color emotions such as the use of red to represent confrontations black to represent the feeling of being lost and green for frightening things
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in making the single bright flight / l miranic she mentions in an interview with hmv japan that the concept of the single is that it can be divided into two parts pink and black pink is the color of bright flight a song which is in a pop style and was written in a cute image in mind while black is the color of l miranic which is in a dark rock style and has the theme of a bad woman lisa mentioned that the name l miranic was chosen because the song is linked to criminals and that since miranic is a name in some countries adding her name to miranic to make lisa @@ miranic would mean that the criminal in the song is her
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dennis amith of j ent reviewed lisa 's album landspace where he describes the song crossing field as a song about wanting to forget the weakness and securities of one past and being with someone you love who gives you the strength to become even stronger meanwhile he describes the song best day best way as a fun and happy track about believing in yourself and overcoming anything bad that have happened in the past and moving forward finally he describes träumerei as another inspirational song about one losing the rhythm in their heart and is now on the road of loneliness but still the person wants to pierce the sky with their own light shatter the darkness and have a fresh new start in life he concludes the review by saying that the album is full of upbeat and inspirational songs and showcases lisa 's talents as a vocalist and in contrast to many <unk> artists who are known for their cute and sweet vocals lisa is able to take on many musical styles
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= = discography = =
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the discography of lisa includes three studio albums one extended play ten singles and five video albums
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studio albums
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lover s mile ( 2012 )
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landspace ( 2013 )
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