Editing Rossmann fold

{{short description|Protein fold}}
{{missing information|more non-nucleotide functions|date=February 2021}}
{{Infobox protein family
| Symbol = NADP_Rossmann
| Name = NAD(P)-binding Rossmann fold
| image = 
| caption = 
| Pfam = 
| Pfam_clan = CL0063
| ECOD = 2003.1
| InterPro = 
| SMART = 
| PROSITE = 
| MEROPS =
| CATH =
| SCOP = 
| TCDB = 
| OPM protein = 
| CAZy = 
| CDD =
}}
{{Infobox protein family
| Name      = Rossmann-like alpha/beta/alpha sandwich fold
| Symbol    = Rossmann-like_a/b/a_fold
| image     = Alcohol dehydrogenase Rossmann.png
| caption   = NAD/NADP binding rossmann fold domains. The picture depicts the beta-alpha folding in alcohol dehydrogenase.
| InterPro  = IPR014729
| Pfam_clan = CL0039
}}
The '''Rossmann fold''' is a tertiary fold found in [[protein]]s that bind [[nucleotide]]s, such as enzyme [[cofactor (biochemistry)|cofactors]] [[flavin adenine dinucleotide|FAD]], [[Nicotinamide adenine dinucleotide|NAD<sup>+</sup>]], and [[NADP|NADP<sup>+</sup>]]. This fold is composed of alternating [[beta strand]]s and [[alpha helical]] segments where the beta strands are hydrogen bonded to each other forming an extended [[beta sheet]] and the alpha helices surround both faces of the sheet to produce a three-layered sandwich. The classical Rossmann fold contains six beta strands whereas Rossmann-like folds, sometimes referred to as '''Rossmannoid folds''', contain only five strands. The initial beta-alpha-beta (bab) fold is the most conserved segment of the Rossmann fold.<ref name="Hanukoglu_2015">{{cite journal | vauthors = Hanukoglu I | title = Proteopedia: Rossmann fold: A beta-alpha-beta fold at dinucleotide binding sites | journal = Biochemistry and Molecular Biology Education | volume = 43 | issue = 3 | pages = 206–9 | year = 2015 | pmid = 25704928 | doi = 10.1002/bmb.20849 | doi-access = free }}</ref> The motif is named after [[Michael Rossmann]] who first noticed this structural motif in the enzyme [[lactate dehydrogenase]] in 1970 and who later observed that this was a frequently occurring motif in nucleotide binding proteins.<ref name = "Lehninger_2013">{{cite book | vauthors = Cox MM, Nelson DL | title = Lehninger Principles of Biochemistry | date = 2013 | publisher = W.H. Freeman | location = New York | isbn = 978-1-4292-3414-6 | edition = 6th }}</ref>

Rossmann and Rossmannoid fold proteins are extremely common. They make up 20% of proteins with known structures in the [[Protein Data Bank]], and are found in more than 38% of [[KEGG]] metabolic pathways.<ref name=Medvedev_2019/> The fold is extremely versatile in that it can accommodate a wide range of ligands. They can function as metabolic enzymes, DNA/RNA binding, and regulatory proteins in addition to the traditional role.<ref name=Med/>

== History ==
The Rossmann fold was first described by Dr. [[Michael Rossmann]] and coworkers in 1974.<ref name="Kessel_2010" /> He was the first to deduce the structure of lactate dehydrogenase and characterized the structural motif within this enzyme which would later be called the Rossmann fold. It was subsequently found that most dehydrogenases that utilize NAD or NADP contain this same structurally conserved Rossmann fold motif.<ref name="Kessel_2010">{{cite book | title = Introduction to Proteins: Structure, Function, and Motion | vauthors = Kessel A | publisher = CRC Press | year = 2010 | isbn = 978-1-4398-1071-2 | location = Florida | pages = 143 }}</ref><ref>{{cite journal | vauthors = Rao ST, Rossmann MG | title = Comparison of super-secondary structures in proteins | journal = Journal of Molecular Biology | volume = 76 | issue = 2 | pages = 241–56 | date = May 1973 | pmid = 4737475 | doi = 10.1016/0022-2836(73)90388-4 }}</ref>

In 1989, [[Israel Hanukoglu]] from the [[Weizmann Institute of Science]] discovered that the consensus sequence for NADP<sup>+</sup> binding site in some enzymes that utilize NADP<sup>+</sup> differs from the NAD<sup>+</sup> binding motif.<ref name="Hanukoglu_1989">{{cite journal | vauthors = Hanukoglu I, Gutfinger T | title = cDNA sequence of adrenodoxin reductase. Identification of NADP-binding sites in oxidoreductases | journal = European Journal of Biochemistry | volume = 180 | issue = 2 | pages = 479–84 | date = March 1989 | pmid = 2924777 | doi = 10.1111/j.1432-1033.1989.tb14671.x | url = https://zenodo.org/record/890733 | doi-access = free }}</ref> This discovery was used to re-engineer coenzyme specificities of enzymes.<ref name="Scrutton_1990">{{cite journal | vauthors = Scrutton NS, Berry A, Perham RN | title = Redesign of the coenzyme specificity of a dehydrogenase by protein engineering | journal = Nature | volume = 343 | issue = 6253 | pages = 38–43 | date = January 1990 | pmid = 2296288 | doi = 10.1038/343038a0 | bibcode = 1990Natur.343...38S | s2cid = 1580419 }}</ref>

== Structure ==
[[File:Rossmann_fold_schematic.svg|thumb|360px|Schematic diagram of a six stranded Rossmann fold]]
{{multiple image
| align       = right
| total_width = 360
| image1      = 5KKA_A_Rossmann_fold_front.png
| width1      = 804 | height1 = 734
| alt1        = Front view
| caption1    = Front view

| image2      = 5KKA_A_Rossmann_fold_side.png
| width2      = 854 | height2 = 716
| alt2        = Side view
| caption2    = Side view
| footer      = Cartoon diagram of the Rossmann fold (helices A-F red and strands 1-6 yellow) from ''[[E. coli]]'' [[malate dehydrogenase]] ({{PDBe-KB|5KKA}}).
}}

The Rossmann fold is composed of six parallel [[beta strand]]s that form an extended [[beta sheet]]. The first three strands are connected by [[Alpha helix|α- helices]] resulting in a beta-alpha-beta-alpha-beta structure.  This pattern is duplicated once to produce an inverted tandem repeat containing six strands. Overall, the strands are arranged in the order of 321456 (1 = N-terminal, 6 = C-terminal).<ref>{{cite web | title = NAD(P)-binding Rossmann-fold domains | work = [[Structural Classification of Proteins database|SCOP: Structural Classification of Proteins]] | url = http://scop.mrc-lmb.cam.ac.uk/scop/data/scop.b.d.c.A.html | access-date = 2017-12-17 | archive-date = 2018-11-21 | archive-url = https://web.archive.org/web/20181121202910/http://scop.mrc-lmb.cam.ac.uk/scop/data/scop.b.d.c.A.html | url-status = dead }}</ref>  Five stranded Rossmann-like folds are arranged in the order 32145.<ref>{{cite web | title = Nucleotide-binding domain | work = [[Structural Classification of Proteins database|SCOP: Structural Classification of Proteins]] | url = http://scop.mrc-lmb.cam.ac.uk/scop/data/scop.b.d.e.A.html | access-date = 2017-12-17 | archive-date = 2018-12-07 | archive-url = https://web.archive.org/web/20181207052012/http://scop.mrc-lmb.cam.ac.uk/scop/data/scop.b.d.e.A.html | url-status = dead }}</ref> The overall tertiary structure of the fold resembles a three-layered sandwich wherein the filling is composed of an extended beta sheet and the two slices of bread are formed by the connecting parallel alpha-helices.<ref name="Hanukoglu_2015" />

One of the features of the Rossmann fold is its [[cofactor (biochemistry)|co-factor]] binding specificity. Through the analysis of four NADH-binding enzymes, it was found that in all four enzymes the nucleotide co-factor entailed the same conformation and orientation with respect to the polypeptide chain.<ref name="Hanukoglu_2015"/>

The fold may contain additional strands joined by short helices or coils.<ref name="Hanukoglu_2015" /> The most conserved segment of Rossmann folds is the first beta-alpha-beta segment. Phosphate-binding loop is located between the first beta-strand and alpha-helix. On the tip of the second beta-strand, there is a conserved aspartate residue that is involved in ribose binding.<ref>{{cite journal | vauthors = Longo LM, Jabłońska J, Vyas P, Kanade M, Kolodny R, Ben-Tal N, Tawfik DS | title = On the emergence of P-Loop NTPase and Rossmann enzymes from a Beta-Alpha-Beta ancestral fragment | journal = eLife | volume = 9 | pages = e64415 | date = December 2020 | pmid = 33295875 | pmc = 7758060 | doi = 10.7554/eLife.64415 | veditors = Deane CM, Boudker O | doi-access = free }}</ref> Since this segment is in contact with the [[Adenosine diphosphate|ADP]] portion of dinucleotides such as [[Flavin adenine dinucleotide|FAD]], [[Nicotinamide adenine dinucleotide|NAD]] and [[Nicotinamide adenine dinucleotide phosphate|NADP]] it is also called as an "ADP-binding beta-beta fold.

== Function ==
The function of the Rossmann fold in enzymes is to bind nucleotide cofactors.  It also often contributes to substrate binding.

Metabolic enzymes normally have one specific function, and in the case of [[UDP-glucose 6-dehydrogenase]], the primary function is to catalyze the two step NAD(+)-dependent oxidation of [[UDP-glucose]] into [[UDP-glucuronic acid]].<ref name="Bhattacharyya_2012">{{cite journal | vauthors = Bhattacharyya M, Upadhyay R, Vishveshwara S | title = Interaction signatures stabilizing the NAD(P)-binding Rossmann fold: a structure network approach | journal = PLOS ONE | volume = 7 | issue = 12 | pages = e51676 | year = 2012 | pmid = 23284738 | pmc = 3524241 | doi = 10.1371/journal.pone.0051676 | bibcode = 2012PLoSO...751676B | doi-access = free }}</ref> The N- and C-terminal domains of UgdG share structural features with ancient mitochondrial ribonucleases named MAR. MARs are present in lower eukaryotic microorganisms, have a Rossmannoid-fold and belong to the isochorismatase superfamily. This observation reinforces that the Rossmann structural motifs found in NAD(+)-dependent dehydrogenases can have a dual function working as a nucleotide cofactor binding domain and as a ribonuclease.

== Evolution ==

=== Rossman and Rossmannoids ===
The evolutionary relationship between the Rossmann fold and Rossmann-like folds is unclear. These folds are referred to as Rossmannoids. It has been hypothesized that all these folds, including a Rossmann fold originated from a single common ancestral fold, that had nucleotide binding capabilities, in addition to non-specific catalytic activity.<ref name="Kessel_2010" />

However, an analysis of the PDB finds evidence of [[convergent evolution]]<ref name=Medvedev_2019>{{cite journal | vauthors = Medvedev KE, Kinch LN, Schaeffer RD, Grishin NV | title = Functional analysis of Rossmann-like domains reveals convergent evolution of topology and reaction pathways | journal = PLOS Computational Biology | volume = 15 | issue = 12 | pages = e1007569 | date = December 2019 | pmid = 31869345 | pmc = 6957218 | doi = 10.1371/journal.pcbi.1007569 | doi-access = free | bibcode = 2019PLSCB..15E7569M }}</ref> with 156 separate H-groups of demonstrable homology, from which 123 X-groups of probable homology can be found. The groups have been integrated into [[ECOD]].<ref name=Med>{{cite journal | vauthors = Medvedev KE, Kinch LN, Dustin Schaeffer R, Pei J, Grishin NV | title = A Fifth of the Protein World: Rossmann-like Proteins as an Evolutionarily Successful Structural unit | journal = Journal of Molecular Biology | volume = 433 | issue = 4 | pages = 166788 | date = February 2021 | pmid = 33387532 | pmc = 7870570 | doi = 10.1016/j.jmb.2020.166788 }}<br />{{cite web | vauthors = Medvedev KE, etal |title=Rossmann-fold project |url=http://prodata.swmed.edu/rossmann_fold/ |work = Grishin Lab | publisher = UT Southwestern Medical Center }}</ref>

=== Conventional Rossman group ===
Phylogenetic analysis of the NADP binding enzyme [[adrenodoxin reductase]] revealed that from prokaryotes, through metazoa and up to primates the sequence motif difference from that of most FAD and NAD-binding sites is strictly conserved.<ref name="Hanukoglu_2017">{{cite journal | vauthors = Hanukoglu I | title = Conservation of the Enzyme-Coenzyme Interfaces in FAD and NADP Binding Adrenodoxin Reductase-A Ubiquitous Enzyme | journal = Journal of Molecular Evolution | volume = 85 | issue= 5 | pages= 205–218 | year= 2017 | pmid= 29177972 | doi= 10.1007/s00239-017-9821-9 | bibcode = 2017JMolE..85..205H | s2cid = 7120148 }}</ref>

In many articles and textbooks, a Rossmann fold is defined as a strict repeated series of βαβ structure. Yet, comprehensive examination of the Rossmann folds in many NAD(P) and FAD binding sites revealed that only the first βα structure is strictly conserved. In some enzymes, there may be many loops and several helices (i.e., not a single helix) between the beta strands that form the beta-sheet.<ref name="Hanukoglu_2015" /> These enzymes have a common origin indicated by conserved sequence and structural features, according to Hanukoglu.<ref name="Hanukoglu_2017" />

The result by Hanukoglu (2017) is corroborated by Medvedev et al. (2020), in the form of an ECOD "H-group" called "[http://prodata.swmed.edu/ecod/complete/tree?id=2003.1 Rossmann-related]". Even within this group, ECOD describes a wide range of non-nucleotide activities.<ref name=Med/>

== References ==
{{Reflist|33em}}

== External links ==
* [http://proteopedia.org/w/Rossmann_fold Proteopedia page on the Rossmann folds]
{{Protein tertiary structure}}

{{DEFAULTSORT:Rossmann Fold}}
[[Category:Protein folds]]
[[Category:Protein structural motifs]]	
[[Category:Protein superfamilies]]