Rossmann fold: Difference between revisions
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Rossmann fold is a super-secondary structure that is characterized by an alternating motif of beta-strand-alpha helix-beta strand secondary structures. Hence this fold is also called a βαβ fold. The β-strands participate in the formation of a β-sheet. The βαβ fold structure is commonly observed in enzymes that have dinucleotide coenzymes, such as FAD, NAD and NADP. | {{BAMBED | ||
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Note: This entry on the Rossmann fold has been published in Biochem. Mol. Biol. Educ.<ref name="Hanukoglu-2015">PMID:25704928</ref>. Please cite it as Biochem. Mol. Biol. Educ. 43:206-209, 2015. | |||
The Rossmann fold is a super-secondary structure that is characterized by an alternating motif of beta-strand-alpha helix-beta strand secondary structures. Hence this fold is also called a βαβ fold. The β-strands participate in the formation of a β-sheet. The βαβ fold structure is commonly observed in enzymes that have dinucleotide coenzymes, such as FAD, NAD and NADP. | |||
==History== | ==History== | ||
[[Image:FAD-NADH-Structures.png|500px|right|thumb| Fig. 1. Structures of FAD and NADH in vertical orientation.]] | [[Image:FAD-NADH-Structures.png|500px|right|thumb| Fig. 1. Structures of FAD and NADH in vertical orientation.]] | ||
In 1973 Rao and Rossmann reported that a βαβ fold super-secondary structure commonly appears in a variety of nucleotide binding proteins, such as lactate dehydrogenase and flavodoxin <ref name="R-R">PMID:4737475</ref>. In later studies this common structure was named after the author Michael G. Rossmann as Rossmann fold. | In 1973 Rao and Rossmann reported that a βαβ fold super-secondary structure commonly appears in a variety of nucleotide binding proteins, such as lactate dehydrogenase and flavodoxin <ref name="R-R">PMID:4737475</ref>. In later studies this common structure was named after the author Michael G. Rossmann as the Rossmann fold. | ||
The βαβ fold structure was initially characterized in dinucleotide FAD and NADH binding proteins. Schulz et al. examining FAD binding domains of four enzymes noted that the βαβ fold structure was associated with a specific consensus sequence of Gly-x-Gly-x-x-Gly at the region of the tight loop between the first β-strand the α-helix <ref>PMID:7175934</ref>. Wierenga et al. systematically examined more structures and derived rules for a fingerprint sequence named "ADP-binding βαβ fold" <ref>PMID:3959077</ref>. | The βαβ fold structure was initially characterized in dinucleotide FAD and NADH binding proteins. Schulz et al. examining FAD binding domains of four enzymes noted that the βαβ fold structure was associated with a specific consensus sequence of Gly-x-Gly-x-x-Gly at the region of the tight loop between the first β-strand the α-helix <ref>PMID:7175934</ref>. Wierenga et al. systematically examined more structures and derived rules for a fingerprint sequence named the "ADP-binding βαβ fold" <ref>PMID:3959077</ref>. | ||
In 1989, Israel Hanukoglu found that NADPH binding βαβ fold in NADP dependent enzymes is characterized by a specific consensus sequence (briefly: Gly-x-Gly-x-x-Ala) that differs from the NADH binding site by one residue, with an alanine instead of the last glycine, and hypothesized that this single residue difference may determine the coenzyme specificity of the enzymes <ref name="HI-1989">PMID:2924777</ref>. Richard Perham and his colleagues confirmed this hypothesis by site-directed mutagenesis of glutathione reductase and showed that coenzyme specificity could be re-engineered from NAD to NADP <ref>PMID:2296288</ref>. The structural significance of the Ala for Gly substitution in NADP binding site was revealed by analysis of the crystal structure of NADP-dependent | In 1989, Israel Hanukoglu found that the NADPH binding βαβ fold in NADP dependent enzymes is characterized by a specific consensus sequence (briefly: Gly-x-Gly-x-x-Ala) that differs from the NADH binding site by one residue, with an alanine instead of the last glycine, and hypothesized that this single residue difference may determine the coenzyme specificity of the enzymes <ref name="HI-1989">PMID:2924777</ref>. Richard Perham and his colleagues confirmed this hypothesis by site-directed mutagenesis of glutathione reductase and showed that coenzyme specificity could be re-engineered from NAD to NADP <ref>PMID:2296288</ref>. The structural significance of the Ala for Gly substitution in NADP binding site was revealed by analysis of the crystal structure of NADP-dependent adrenodoxin-reductase <ref name="Ziegler-1999">PMID:10369776</ref>. | ||
==Dinucleotides that bind to Rossmann fold== | ==Dinucleotides that bind to Rossmann fold== | ||
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Note that both dinucleotides share at their base the common structure of adenosine diphosphate (ADP). The structure of FAD can be viewed either as a hybrid of AMP+FMN or as ADP+Riboflavin (see figure). | Note that both dinucleotides share at their base the common structure of adenosine diphosphate (ADP). The structure of FAD can be viewed either as a hybrid of AMP+FMN or as ADP+Riboflavin (see figure). | ||
NAD(P) is a two electron acceptor and donates the two electrons to FAD. The transfer of electrons takes place from C4 of NAD(P) to N5 of FAD. | NAD(P) is a two electron acceptor and donates the two electrons to FAD. The transfer of electrons takes place from C4 of NAD(P) to N5 of FAD. Each of these atoms is marked by its respective number in Figure 1. | ||
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==Contact region between Rossmann fold and FAD== | ==Contact region between Rossmann fold and FAD== | ||
[[Image:FAD-binding-sites.png|500px|right|thumb| Fig. 2. FAD binding sites of D-amino acid oxidase ( | [[Image:FAD-binding-sites.png|500px|right|thumb| Fig. 2. The FAD binding sites of D-amino acid oxidase ([[2e48]]) (residues 1-36) and glutathione reductase ([[3grs]]) (residues 21-50). FAD is shown in CPK mode.]] | ||
In dinucleotide binding flavoproteins, FAD binding Rossmann fold is commonly located close to the amino terminus of the protein. Figure 2 shows the first Rossmann fold of two flavoproteins, D-amino acid oxidase (2e48)<ref>PMID:17303072</ref> and glutathione reductase ( | In dinucleotide binding flavoproteins, FAD binding Rossmann fold is commonly located close to the amino terminus of the protein. Figure 2 shows the first Rossmann fold of two flavoproteins, D-amino acid oxidase ([[2e48]])<ref>PMID:17303072</ref> and glutathione reductase ([[3grs]])<ref>PMID:3656429</ref>. In both enzymes, the first β-strand is followed by a tight loop that is connected to the N-terminal of the helix. The two highly conserved Gly residues in the consensus sequence are located in this turn to allow the sharp bending of the chain. At the end of the helix there is a wider turn that is followed by the second beta strand that runs parallel to the first strand. | ||
The FAD structure is shown in CPK format. The atoms can be identified by their colors: <span style="color:Gray">Carbon</span>; <span style="color:red">Oxygen</span>, <span style="color:DarkOrange">Phosphorus</span> and <span style="color:SlateBlue">Nitrogen</span>. The turn at the β-α border is in contact with the negatively charged <span style="color:red">oxygens</span> of the two <span style="color:DarkOrange">phosphate</span> groups. | |||
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==Contact region between Rossmann fold and NAD(P)== | |||
[[Image:NAD-binding-sites.png|500px|right|thumb| Fig. 3. NAD binding sites of 3-phosphoglycerate dehydrogenase ([[2p9e]]) (residues 152-182) and lactate dehydrogenase ([[1i0z]]). NAD is shown in CPK mode.]] | |||
Figure 3 shows the Rossmann fold of two NAD binding proteins, 3-phosphoglycerate dehydrogenase ([[2p9e]])<ref>PMID:17459882</ref> and lactate dehydrogenase ([[1i0z]]) (residues 21-53) <ref>PMID:11276087</ref>. In enzymes that have just an NAD binding site, the site may be close to the N terminus of the protein as in lactate dehydrogenase. In flavoproteins that bind two dinucleotides, such as glutathione reductase and adrenodoxin reductase <ref name="HI-1989" />, the NAD(P) binding site appears in the middle of the protein. | |||
The βαβ fold has a structure similar to the fold shown above for FAD. For both enzymes, the first β-strand is followed by a tight turn that is connected to the N-terminal of the helix. The same Gly-x-Gly-x-x-Gly consensus sequence appears at the turn between the first strand and the helix. Again, similar to FAD site, the turn region is in contact with the negatively charged <span style="color:red">oxygens</span> of the two <span style="color:DarkOrange">phosphate</span> groups. | |||
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==A βαβ fold example in ferredoxin reductase == | |||
To illustrate a βαβ fold in a complete protein, a 3D example (PDB ID: [[1f3p]]) is shown below. The example protein is a ferredoxin reductase from Pseudomonas that binds both an FAD and NADH <ref>PMID:11090282</ref>. This enzyme binds NADH which transfers its two electrons to the FAD coenzyme of ferredoxin reductase. These electrons are then transferred to a ferredoxin that is an iron sulfur electron transfer protein. This ferredoxin then donates the electrons to an oxygenase that uses the electrons in a dioxygenase reaction. | |||
In Fig. 4 below, the two core β-strands of the FAD binding site of the enzyme (PDB ID: [[1f3p]]) are shown in cyan ( <span style="color:Cyan">██</span> ) colored "rocket" format, with a red colored helix in between the two strands. | |||
<Structure load='1f3p' size='500' frame='true' align='left' caption='Fig. 4. FAD binding site of ferredoxin reductase. PDB ID: 1f3p.' scene='59/595757/Ferredoxin-reductase-fad/2' /> | |||
The following scenes illustrate some aspects of the structure. | |||
As noted above, the Rossmann fold is associated with a specific consensus sequence of Gly-x-Gly-x-x-Gly at the region of the tight loop between the first β-strand the α-helix. | |||
The first two scenes demonstrate the location of the first two conserved glycines. | |||
To rotate the molecule click and hold left mouse button. | |||
To zoom-in or zoom-out first click on the structure and then use the mouse wheel. | |||
Click the following green links for the action indicated: | |||
<scene name='59/595757/Ferredoxin-reductase-fad-gly14/2'> | : * <scene name='59/595757/Ferredoxin-reductase-fad-gly14/2'>Display the first conserved glycine in space filling CPK format at the end of the first beta-strand of the FAD binding site.</scene> | ||
<scene name='59/595757/Ferredoxin-reductase-fad-gly16/ | : * <scene name='59/595757/Ferredoxin-reductase-fad-gly16/4'>Display the second conserved glycine in space filling CPK format at the beginning of the helix of the FAD binding site.</scene> | ||
<scene name='59/595757/Ferredoxin-reductase-fad-5-78/1'> | : * <scene name='59/595757/Ferredoxin-reductase-fad-5-78/1'>Display the structure of the residues 5-78.</scene> Note that in between the second β-strand and the third one there are four α-helical segments. | ||
: * <scene name='59/595757/Ferredoxin-reductase-full/3'>Display the full structure of ferredoxin reductase.</scene> Note that FAD has been colored a yellowish green ( <span style="color:GreenYellow">██</span> ), and NADP is shown also in CPK format that neighbors FAD. | |||
Note that in the full structure there are 5 β-strands that form a β-sheet in the FAD domain Rossmann fold. | |||
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==Extension of the beta sheet by additional strands== | ==Extension of the beta sheet by additional strands== | ||
[[Image:3-phosphoglycerate_dehydrogenase-2P9E-sheet.png|400px|right|thumb| Fig. | [[Image:3-phosphoglycerate_dehydrogenase-2P9E-sheet.png|400px|right|thumb| Fig. 5. 3-phosphoglycerate dehydrogenase ([[2p9e]]) beta sheet in the NAD binding domain. The two beta-strands that form the core of the Rossmann fold are marked in dark-blue ( <span style="color:MediumBlue">██</span> )color.]] | ||
In many (but not all) proteins with βαβ fold, the β-strands may be part of a larger β-sheet with up to seven β-strands. Figure | As seen in the above example of ferredoxin reductase the β-sheet that is in the nucleotide domain may have more than two strands. In many (but not all) proteins with βαβ fold, the β-strands may be part of a larger β-sheet with up to seven β-strands. Figure 5 shows five strands forming a β-sheet in phosphoglycerate dehydrogenase ([[2p9e]]). Note that the segment connecting the second strand to the third is in coiled confirmation and not helical. Whereas the subsequent connections between strands include α-helix segments. | ||
As seen in the example in Fig. 5, the direction of the strands are all parallel. This represents a general trend in Rossmann folds. However in some Rossmann folds there may be some strands in anti-parallel direction.<ref name="Hanukoglu-2015" /> | |||
As compared to the direction of the β-strands, the direction of the helical segments is generally anti-parallel to the β-strands (Fig. 5). | |||
In some Rossmann fold domains, the segments in between the β-strands may include a complex series of helical and coiled segments (for example see [[3bhi]]). | |||
==Evolutionary origin of the βαβ fold == | ==Evolutionary origin of the βαβ fold == | ||
A myriad of proteins include the βαβ Rossmann fold. Many of these proteins can be grouped in a hierarchy of families based on their sequence similarities <ref>PMID:11514662</ref>,<ref>PMID:8749365</ref>,<ref>PMID:17658942</ref>. Yet, many of these families do not show any significant sequence homology across families. | A myriad of proteins include the βαβ Rossmann fold. Proteopedia includes a list of over 1,000 PDB structures with [[:Category:Rossmann fold | Rossmann fold]]. Many of these proteins can be grouped in a hierarchy of families based on their sequence similarities <ref>PMID:11514662</ref>,<ref>PMID:8749365</ref>,<ref>PMID:17658942</ref>. Yet, many of these families do not show any significant sequence homology across families. | ||
The observation that the βαβ structure and its consensus sequence is observed in many seemingly unrelated proteins raises the question whether the origin of the βαβ fold of all these proteins is a common ancestral sequence. Alternatively, there is also a possibility that this structure emerged in different proteins independently. | The observation that the βαβ structure and its consensus sequence is observed in many seemingly unrelated proteins raises the question whether the origin of the βαβ fold of all these proteins is a common ancestral sequence. Alternatively, there is also a possibility that this structure emerged in different proteins independently. | ||
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==References== | ==References== | ||
<references /> | <references /> | ||
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[[Category: Rossmann fold]] | |||
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