Periplasmic dipeptide-binding protein: Difference between revisions
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== Introduction == | == Introduction == | ||
<Structure load='6E3D' size='350' frame='true' align='right' caption='DppA' scene='Insert optional scene name here' /> | <Structure load='6E3D' size='350' frame='true' align='right' caption='DppA (grey) complex with tetra-peptide (green) (PDB code [[6e3d]])' scene='Insert optional scene name here' /> | ||
Pathogenic bacteria require several metal cofactors for enzymatic activity and, therein, performance of biochemical processes. As a result, these parasites have evolved mechanisms by which they can uptake essential nutrients from their host. Though many of these nutrients are present as ions in the cytosol of host cells or in the extracellular matrix of host tissue at various concentrations, thereby making sequestering these materials relatively simple, iron presents an interesting obstacle in terms of accessibility for bacteria. Iron in eukaryotes exists mainly in erythrocytes in the heme compound hemoglobin, though it also exists in storage compounds such as ferritin, lactoferrin, transferrin, and hemosiderin<ref>Ems, Thomas. “Biochemistry, Iron Absorption.” StatPearls [Internet]., U.S. National Library of | Pathogenic bacteria require several metal cofactors for enzymatic activity and, therein, performance of biochemical processes. As a result, these parasites have evolved mechanisms by which they can uptake essential nutrients from their host. Though many of these nutrients are present as ions in the cytosol of host cells or in the extracellular matrix of host tissue at various concentrations, thereby making sequestering these materials relatively simple, iron presents an interesting obstacle in terms of accessibility for bacteria. Iron in eukaryotes exists mainly in erythrocytes in the heme compound hemoglobin, though it also exists in storage compounds such as ferritin, lactoferrin, transferrin, and hemosiderin<ref>Ems, Thomas. “Biochemistry, Iron Absorption.” StatPearls [Internet]., U.S. National Library of | ||
Medicine, 21 Apr. 2019, www.ncbi.nlm.nih.gov/books/NBK448204/.</ref>. As a result, pathogens have evolved several means by which facilitated transport of heme and hemoglobin occurs for subsequent heme and hemoglobin degradation. | Medicine, 21 Apr. 2019, www.ncbi.nlm.nih.gov/books/NBK448204/.</ref>. As a result, pathogens have evolved several means by which facilitated transport of heme and hemoglobin occurs for subsequent heme and hemoglobin degradation. | ||
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== ''M. tuberculosis'' and Iron Uptake == | == ''M. tuberculosis'' and Iron Uptake == | ||
''Mycobacterium tuberculosis'' (Mtb) is a droplet-spread bacteria which causes tuberculosis. The bacterium lives and reproduces within the phagosomes of alveolar macrophages. In 2018 alone, nearly 1.5 million people died from tuberculosis, making it among the top 10 diseases in terms of mortality<ref>“Tuberculosis (TB).” World Health Organization, World Health Organization, | ''Mycobacterium tuberculosis'' (Mtb) is a droplet-spread bacteria which causes tuberculosis. The bacterium lives and reproduces within the phagosomes of alveolar macrophages. In 2018 alone, nearly 1.5 million people died from tuberculosis, making it among the top 10 diseases in terms of mortality<ref>“Tuberculosis (TB).” World Health Organization, World Health Organization, | ||
www.who.int/news-room/fact-sheets/detail/tuberculosis.</ref>. Being that iron is relatively scarce within alveolar macrophage phagosomes, Mtb has evolved intricate means by which iron is uptaken. The sheer number of genes dedicated to these processes is an indication of the complex evolution of this uptake. For instance, | www.who.int/news-room/fact-sheets/detail/tuberculosis.</ref>. Being that iron is relatively scarce within alveolar macrophage phagosomes, Mtb has evolved intricate means by which iron is uptaken. The sheer number of genes dedicated to these processes is an indication of the complex evolution of this uptake. For instance, approximately 35 known genes in the Mtb genome are associated only with the production of salicylate-derivative iron siderophores termed mycobactins<ref>DOI: 10.1086/518040</ref>. | ||
== Heme Transport Into Mtb == | == Heme Transport Into Mtb == | ||
Mtb has a two-membrane exterior, composed of a peptidoglycan exterior membrane and an interior cell membrane. Heme transport into the periplasmic space has been understood for some time in that several integral proteins used in the transport of heme from the extracellular matrix into the periplasmic space have been elucidated, specifically PPE36, PPE22, and PPE62<ref name=Alex>DOI: 10.1038/s41467-019-12109-5</ref>. DppA is a type of periplasmic binding protein specific to Mtb. | |||
== Periplasmic Binding Proteins (PBPs) == | == Periplasmic Binding Proteins (PBPs) == | ||
Periplasmic binding proteins (PBPs) are non-enzymatic receptors that bacteria use to sense small molecules such as carbohydrates, amino acids, and ions, and transport them into the cytoplasm<ref name=ACS>DOI: 10.1021/cb900021q</ref>. These sorts of proteins are ubiquitous in both gram-negative and gram-positive bacteria, appearing in gram-positive bacteria as membrane-anchored lipoproteins<ref name=ACS/>. The glucose/galactose binding protein (<scene name='84/842887/Gbbp/4'>GBBP</scene>) of ''E. coli'' is amongst the best studied of these proteins<ref>DOI: 10.1016/j.cbpa.2013.12.014</ref>. These proteins typically exhibit a “Venus fly-trap” appearance, consisting of two globular domains connected by a small hinge region<ref name=ACS/>. The hinge-like appearance is evident in GBBP. These proteins often also work in conjunction with an ABC-binding cassette transporter which catalyzes the movement of the substance at hand across the cytoplasmic membrane. | '''Periplasmic binding proteins''' (PBPs) are non-enzymatic receptors that bacteria use to sense small molecules such as carbohydrates, amino acids, and ions, and transport them into the cytoplasm<ref name=ACS>DOI: 10.1021/cb900021q</ref>. These sorts of proteins are ubiquitous in both gram-negative and gram-positive bacteria, appearing in gram-positive bacteria as membrane-anchored lipoproteins<ref name=ACS/>. The glucose/galactose binding protein (<scene name='84/842887/Gbbp/4'>GBBP</scene>) of ''E. coli'' is amongst the best studied of these proteins<ref>DOI: 10.1016/j.cbpa.2013.12.014</ref>. These proteins typically exhibit a “Venus fly-trap” appearance, consisting of two globular domains connected by a small hinge region<ref name=ACS/>. The hinge-like appearance is evident in GBBP. These proteins often also work in conjunction with an ABC-binding cassette transporter which catalyzes the movement of the substance at hand across the cytoplasmic membrane. | ||
== Other Heme Binding PBPs == | == Other Heme Binding PBPs == | ||
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== DPP System in Mtb == | == DPP System in Mtb == | ||
The DPP system in Mtb is used for influx of heme across the cellular membrane. DppA is a member of the DPP system in Mtb. DppA transports heme across the periplasmic space of Mtb to the DppBCD transporter, which likely transfers the heme across the membrane as has been seen with other substrate-binding proteins of ABC transporters<ref name=Alex/>. Research has shown the DPP complex is not involved in heme detoxification, but rather is involved in the import of heme across the cell membrane<ref name=Alex/>. | The DPP system in Mtb is used for influx of heme across the cellular membrane. DppA is a member of the DPP system in Mtb. '''DppA''' or '''periplasmic dipeptide-binding protein''' or '''ABC transporter-associated periplasmic dipeptide-binding protein'''transports heme across the periplasmic space of Mtb to the DppBCD transporter, which likely transfers the heme across the membrane as has been seen with other substrate-binding proteins of ABC transporters<ref name=Alex/>. Research has shown the DPP complex is not involved in heme detoxification, but rather is involved in the import of heme across the cell membrane<ref name=Alex/>. | ||
== General Information about DppA == | == General Information about DppA == | ||
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== Genetic Homology with Other PBPs == | == Genetic Homology with Other PBPs == | ||
Other periplasmic binding proteins have been isolated and studied. DppA shares no homology with HemT of ''S. marcescens''<ref name=Alex/>. The | Other periplasmic binding proteins have been isolated and studied. DppA shares no homology with HemT of ''S. marcescens''<ref name=Alex/>. The Mtb rv3666c-rv3663c operon, though, does encode four proteins that share ~25-45% sequence similarity with DPP dipeptide transporter of ''E. coli'', which similarly transports hemoglobin through the periplasmic space<ref name=Alex/>. | ||
== Structural Homology with Other PBPs == | == Structural Homology with Other PBPs == | ||
DppA is similar structurally to a few homologous proteins, especially to the ''S. typhimurium'' ortholog that superimposes the structure with an RMSD ~1.45Å<ref name=Alex/>. | DppA is similar structurally to a few homologous proteins, especially to the ''S. typhimurium'' ortholog that superimposes the structure with an RMSD ~1.45Å<ref name=Alex/>. | ||
==3D structures of periplasmic dipeptide-binding protein== | |||
See [[ABC transporter 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||