Elizeu/sandbox/citocromo c

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NCBI Accession: P42363.1

Uniprot Accesion: POA4G2

PDB ID: 3H90

1 Overview
- 1.1 General Structure
2 Interaction of Dimers
- 2.1 Salt Bridges
- 2.2 Electrostatic Interactions
3 Function
4 Interactions with other proteins
5 Disease
- 5.1 Otitis media
- 5.2 Pneumonia
6 Application in Biotechnology
7 References

Overview

Structural Transporter Yiip

General Structure

yiip has two dimers, connected by salt bridges in the alpha helices

Interaction of Dimers

the dimers interact via salt bridges and electrostatic interactions

Salt Bridges

insert photo and explanation here

Electrostatic Interactions

Cadmium uptake reduces the millimolar cellular accumulation of manganese and zinc, and thereby increases sensitivity to oxidative stress ^[1].

Ramachandran blot of PsaA obtained by Lovell, Davis, et al. Proteins 50:437

Function

Mn²⁺ enables Streptococcus Pneunomiae to have a prompt and rapid growth. Superoxides are a key player in oxidative stress generated in the presence of iron. Therefore PsaA is essential for the existence of S. pneumoniae as mutations in the psaA gene cause deficiencies in growth but also in its virulence, adherence and the response to oxidative stress.

Adhesin and virulence

PsaA is well hidden beneath the cell wall and the polysaccharide capsule, which is why it does not directly act as an adhesin as initially assumed. This was confirmed by studies on psaB and psaC deletion mutants which were not deficient in PsaA but showed impaired adherence, similar to psaA deletion mutants. As the disruption of either of the members of the Psa operon affects pneumococcal adherence, it seems that this process is coupled to the cellular Mn²⁺ transport system. With bacterial adhesion being the first step in bacterial pathogenesis, the extinction of PsaA and the associated Psa operon lead to attenuated virulence in affected strains ^[2].

Virulence

Next to its involvement in bacterial adhesion and the colonization in the human nasopharynx, S. pneumoniae actively produces H2O2 in large amounts to augment its own virulence on the one hand, and, on the other hand, to utilize it as a weapon in the competition against other pathogens ^[2]. Mn²⁺ is also required for the activity of CpsB, a tyrosine phosphatase involved in the regulation of capsule production. And in some streptococcal species, lectin-mediated adherence requires Mn²⁺. Finally, mutations in the psaBCA operon result in an almost complete attenuation of virulence for all tested models of animal infection.

Oxidative stress

In S. pneumoniae H2O2 and superoxides are generated as toxic derivatives of molecular oxygen in several metabolic processes and during growth by pyruvate oxidase. Subsequently, H2O2 reacts with Fe²⁺ during the Fenton reaction. This results in the formation of the hydroxylyl radical that causes severe damages in the cell. As a protective response against this oxidative stress, S. pneumoniae produces an Mn²⁺-dependent superoxide dismutase (SodA) and the thiol peroxidase encoded by psaD in the Psa operon. Due to the use of H2O2 during pneumococcal virulence these two proteins and the dependence on Mn²⁺ are of major importance. When Mn²⁺ transport is disrupted, bacterial cells display hypersensitivity towards oxidative stress ^[2].

Interactions with other proteins

- piaA, pneumococcal iron acquisition A which is an iron-compound ABC transporter permease. It is required for bacterial growth and full virulence in pulmonary infection.

-pavA, Pneumococcal adherence and virulence factor A is an adherence and virulence protein A. It binds fibronectin.

-Wzg, which regulates the capsule production and is an integral membrane regulatory protein Cps2A

-Tpx, a thiol peroxidase with a Has antioxidant activity. This protein can remove peroxides or H2O2 by similarity.

-PsaC, a manganese ABC transporter permease

-PsaB, a manganese ABC transporter ATP-binding protein. Deleting psaB results in decreased expression of PsaA. PsaC and psaC require Mn²⁺ supplementation for growth and transformation.

-SPD_1450, an iron-dependent transcriptional regulator

-adcC, antibody-dependent cell-mediated cytotoxicity is a zinc ABC transporter ATP-binding protein.

-adcB, a zinc ABC transporter permease

Disease

Otitis media

PsaA has been recognized to be involved in the adherence and virulence mechanisms of otitis media. Streptococcus pneumoniae is one of the main agents causing bacterial acute otitis media, directly or as complication of a viral upper respiratory tract infection. This disease is a highly prevalent pediatric disease worldwide. Hearing loss is a common problem associated with this disease. Streptococcus pneumoniae in middle ear can be resistant to penicillin and cephalosporin^[3]

Pneumonia

PsaA protein is an indirect adhesin which is involved in colonization of the nasopharyngeal mucosal. Moreover, alveolar pneumonia is caused by the spread of Streptococcus pneumoniae from nasopharynx. Therefore PsaA protein is involved in infection of pulmonary parenchyma by Streptococcus pneumoniae. Sometimes, Streptococcus pneumoniae pass into the blood and causes a bacteremia besides pneumonia.

Application in Biotechnology

PsaA is being actively evaluated as a component of a vaccin in formulations composed of pneumococcal common proteins. PsaA is a component of a vaccin because this protein is immunogenic and stimulates an increase in antibody production when the nasopharynx is naturally colonized. PsaA has been expressed as an E.coli recombinant protein, purified, and evaluated in a phase one clinical trial. Progress in vaccine development is most advanced for Streptococcus pneumoniae. Indeed, there is a seven-valent capsular-conjugate vaccine, PREVNAR® but it is rather non efficient for otitis media.^[4] PsaA has been shown to be an effective vaccine in animal models at preventing Streptococcus pneumoniae infection. <math>Insert formula here</math>

References

↑ http://www.nature.com/articles/ncomms7418
↑ Cite error: Invalid <ref> tag; no text was provided for refs named ref3
↑ https://www.google.com/patents/US20130078254
↑ Wald ER, Mason EO Jr, Bradley JS, Barson WJ, Kaplan SL. Acute otitis media caused by Streptococcus pneumoniae in children's hospitals between 1994 and 1997. Pediatr Infect Dis J. 2001 Jan;20(1):34-9. PMID:11176564

Proteopedia Page Contributors and Editors (what is this?)

Julie Langlois, Atena Farhangian, Rebecca Holstein, Elizabeth A. Dunlap, Katherine Reynolds, Elizeu Santos, Noam Gonen, Anna Lohning, Idan Ben-Nachum, Brian Ochoa, Shai Biran, Gauri Misra, Shira Weingarten-Gabbay, Keni Vidilaseris, Jamie Costa, Abhinav Mittal, Urs Leisinger, Madison Walberry, Edmond R Atalla, Brett M. Thumm, Brooke Fenn, Joel L. Sussman, Mati Cohen, Vesta Nwankwo, Dotan Shaniv, Gulalai Shah

Retrieved from "http://52.214.119.220/wiki/index.php/Elizeu/sandbox/citocromo_c"

@@ Line 3: / Line 3: @@
 '''Uniprot Accesion:''' POA4G2
-'''PDB ID''': 3ZK7
+'''PDB ID''': 3H90
-<StructureSection load='3zk7' size='350' color='white' side='right' frame='true' caption='3D structure of PsaA in the metal-free, open state (PDB: [http://www.rcsb.org/pdb/explore.do?structureId=3zk7 3zk7])' >
+<Structure load='3H90' size='350' frame='true' align='right' caption='3D image of structural transporter Yiip'/>
-== Overview ==
-'''[[Image:streptococcus pneumoniae.jpg | 250px|thumb| ''Streptococcus pneumoniae'' <ref>http://www.sciencephoto.com/images/download_lo_res.html?id=662360183</ref>]] PsaA (Pneumococcal surface antigen A) is a high affinity substrate-binding lipoprotein <ref name="ref5">http://www.uniprot.org/uniprot/P0A4G2</ref> detected on all known serotypes of [https://en.wikipedia.org/wiki/Streptococcus_pneumoniae ''Streptococcus pneumonia'']. It facilitates the acquisition of Mn<sup>2+</sup> by being part of the cell's [https://de.wikipedia.org/wiki/ABC-Transporter ABC (ATP binding cassette) transporter] and plays a major role in pneumococcal attachment to the host cell and [https://en.wikipedia.org/wiki/Virulence virulence] <ref>PMID:25786639</ref>.'''
-''Streptococcus pneumoniae'', also widely known as pneumococcus, is a Gram positive coccus with a diameter of 0.5 to 1 μm. As a member of the genus ''Streptococcus'' it typically forms diplococci and can live both under aerobic or anaerobic conditions. In healthy carriers it resides in the nasopharynx <ref name="ref4">PMID:4366526</ref>. However, the bacterium may become pathogenic in elderly and [https://en.wikipedia.org/wiki/Immunodeficiency immunocompromised] people as well as in children due to a weaker immune system. In fact, ''S. pneumoniae'' is the most frequent opportunistic pathogen worldwide and causes many types of diseases including [https://en.wikipedia.org/wiki/Otitis_media otitis media], [https://en.wikipedia.org/wiki/Meningitis meningitis], [https://en.wikipedia.org/wiki/Sepsis sepsis] and [https://en.wikipedia.org/wiki/Pneumonia pneumonia] <ref>PMID:26379256</ref>. The genome of ''S. pneumoniae'' is a closed, circular DNA structure that contains between 2.0 and 2.1 million base pairs <ref name="ref4" />.
+== Overview ==
-[[Image:PsaA dans ABC transporteur.jpg |500px|thumb| Structure of ABC-transporter <ref>http://www.latrobe.edu.au/biochemistry-and-genetics/research/maher/psabca-manganese-uptake-by-streptococcus-pneumoniae</ref>]]
+'''[[Image:3h90.0 chimera tm 350 350.png]] Structural Transporter Yiip
-===ABC transporter===
-Bacterial [https://en.wikipedia.org/wiki/ATP-binding_cassette_transporter ABC transporters] are an important class of transmembrane proteins. They are involved in the import and export of a wide variety of substrates, including sugars, amino acids, peptides, [https://en.wikipedia.org/wiki/Polyamine polyamines], and cations <ref>PMID:2715661</ref>. They can be considered as a promising target for antimicrobial strategies. ABC transporters consist of four membrane-associated proteins with two ATP-binding proteins ([https://en.wikipedia.org/wiki/ATPase ATPases]) and two [https://en.wikipedia.org/wiki/Permease permeases]. <ref>http://webcache.googleusercontent.com/search?q=cache:3MvkKDHQVzwJ:www.omicsonline.com/open-access/role-of-abc-transporter-proteins-in-stress-responses-of-streptococcus-mutans-2247-2452.1000592.pdf+&cd=1&hl=fr&ct=clnk&gl=fr&client=firefox-b </ref>
+===General Structure===
+yiip has two dimers, connected by salt bridges in the alpha helices
-In the case of [https://www.wikigenes.org/e/gene/e/2717000.html PsaA], the ABC transporter is composed of an ATP-binding protein (''PsaB''), an integral membrane protein (''PsaC'') and PsaA itself as a [https://en.wikipedia.org/wiki/Lipoprotein lipoprotein] that possess a metal-ion binding site. This confers the protein to bind divalent metal-ions, however, with a preference for Mn<sup>2+</sup> <ref>PMID:18340341</ref>.
-The genes that encode for the components of the ABC transport system are ''psaA'', ''psaB'' and ''psaC'', respectively. They are organized consecutively in the psaBCA operon, together with ''psaD'', the gene encoding for a [[thiol peroxidase]] (see below). <ref name="ref3">PMID:517531</ref>.
-[[Image:operon psa.jpg |600px|center| thumb| PsaBCA operon <ref>PMID:15255900</ref>]]
-=== Binding of zinc ===
+== Interaction of Dimers ==
+the dimers interact via salt bridges and electrostatic interactions
+=== Salt Bridges ===
-Zinc in excess has a significant toxicity to bacteria because it is an important innate defense mechanism. There are many zinc molecules in the human body which compete with manganese for PsaA binding. However manganese has a higher affinity for PsaA while zinc is not transported by the ABC-transporter. Nevertheless, the competition by zinc reduces intracellular manganese concentrations, resulting in the up-regulation of PsaBCA operon expression. <ref>PMID:22072971</ref>
+insert photo and explanation here
+=== Electrostatic Interactions ===
-== General Structure ==
-The protein PsaA has a molecular weight of 34.538 kDa with 309 residues <ref>https://www.mybiosource.com/prods/Recombinant-Protein/Manganese-ABC-transporter-substrate-binding-lipoprotein-psaA/psaA</ref>. The overall size of the protein approximated from its crystal structure is 40 by 40 by 70 Å <ref name="ref1">PMID:28011228</ref>.
-As a member of the Lipoprotein receptor-associated antigen I (LraI) family, the PsaA molecule contains four distinct regions. An N-terminal leader sequence of 20 amino acids holds an LxACy consensus sequence that is recognized and cleaved by signal peptidase II <ref name="ref1" />. A lipid moiety (diacylglycerol <ref name="ref2">PMID:99024</ref>) is added to the cysteine residue and mediates the anchorage of the protein to the cytoplasmic membrane. Apart from this leader sequence, the rest of the protein consists of two twofold-pseudosymmetrical (β/α)<sub>4</sub> sandwich domains, of which the β-strands of each domain form parallel β-sheets <ref name="ref2" />. In total these domains form two lobes connected via an α-helical linker which constitutes the solute-binding site <ref name="ref1" />.
-'''Secondary structure of PsaA:'''
-[[Image:structure secondaire.jpg |1000 px|center| thumb| Secondary structure of PsaA <ref name="ref5" />]]
-We can see on the right, the 3D structure of PsaA protein. We can observe that there are <scene name='55/559112/3zk7_tris/1'>TRIS molecules</scene>(TRIS significate 2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL).
-We can see the <scene name='55/559112/3ztt/1'>3D structure of PsaA with manganese</scene>. Manganese ions are shown as
-<scene name='55/559112/3ztt_purple_sphere/1'>purple spheres</scene>.
-{|
-| [[Image:molec.jpg|left|300px | thumb| 3D structure of PsaA with 2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL (tris) and cadmium <ref>http://www.ebi.ac.uk/pdbe/entry/pdb/4UTO</ref>]]
-| [[Image:showNew.jpg| 250px| thumb| Structure of Tris PsaA needs to be linked to this molecule to be in an open state]]
-|}
-The metal binding site is formed by the side chains of residues His67, His139, Glu205, and Asp280. This site has a tetrahedral coordination geometry. The amino acids His67 and His139 interact with the metal via Nε2 nitrogen atoms while the carboxylate side chains of Glu205 and Asp280 interact with the metal via their Oε1 and Oδ2 atoms. The atomic distance between His67 Nε2 and the metal is 1.99 Ắ while it is 2,01 Ắ for His 139 Nε2. It is 2,04 Ắ for Glu205 Oε1 and 2,02 Ắ for Asp280 Oδ2. The Oδ1 atom of Asp137 can form a hydrogen bond with Nδ1 of His139. Oδ1 atom of Asp65 can also form a hydrogen bond with His67 N. These interactions render PsaA its specificity to bind Mn<sup>2+</sup>, but also allows the binding for Zn<sup>2+</sup> <ref>PMID:9862808</ref>.
+<Structure load='Insert PDB code or filename here' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' />
 Cadmium uptake reduces the millimolar cellular accumulation of manganese and zinc, and thereby increases sensitivity to oxidative stress <ref>http://www.nature.com/articles/ncomms7418</ref>.