Editing Globin

{{Short description|Superfamily of oxygen-transporting globular proteins}}
{{distinguish|globulin|globular protein}}

{{Infobox protein family
| Symbol = Globin
| Name = Globin family (family M)
| image = PDB 1hba EBI.jpg
| width = 
| caption = the Structure of deoxyhemoglobin Rothschild 37 beta Trp----Arg: a mutation that creates an intersubunit chloride-binding site.<ref name="pmid1567857">{{cite journal |vauthors=Kavanaugh JS, Rogers PH, Case DA, Arnone A |title=High-resolution X-ray study of deoxyhemoglobin Rothschild 37 beta Trp----Arg: a mutation that creates an intersubunit chloride-binding site |journal=Biochemistry |volume=31 |issue=16 |pages=4111–21 |date=April 1992 |pmid=1567857 |doi= 10.1021/bi00131a030}}</ref>
| Pfam = PF00042
| Pfam_clan = CL0090
| ECOD = 106.1.1
| InterPro = IPR000971
| SMART =
| PROSITE = PS01033
| SCOP = 1hba
| TCDB = 
| CDD = cd01040
}}
{{Infobox protein family
| Symbol = Bac_globin
| Name = Bacterial-like Globin (family T)
| image = PDB 1s56 EBI.jpg
| width = 
| caption = crystal structure of "truncated" hemoglobin n (hbn) from mycobacterium tuberculosis, soaked with xe atoms
| Pfam = PF01152
| Pfam_clan = CL0090 
| SMART = 
| PROSITE = PDOC00933
| MEROPS = 
| SCOP = 1dlw
| TCDB = 
| OPM family = 
| OPM protein = 
| CAZy = 
| CDD = cd14756
| InterPro = IPR001486
}}
{{Infobox protein family
| Symbol = Protoglobin
| Name = Protoglobin (family S)
| image = 
| width = 
| caption = 
| Pfam = PF11563
| Pfam_clan = CL0090 
| SMART = 
| PROSITE = 
| MEROPS = 
| SCOP = 
| TCDB = 
| OPM family = 
| OPM protein = 
| CAZy = 
| CDD = cd01068
| InterPro = IPR012102
}}
The '''globins''' are a [[Protein superfamily|superfamily]] of [[heme]]-containing [[globular protein]]s, involved in [[Binding (molecular)|binding]] and/or transporting [[oxygen]]. These proteins all incorporate the globin fold, a series of eight [[Alpha helix|alpha helical segments]]. Two prominent members include [[myoglobin]] and [[hemoglobin]]. Both of these proteins reversibly bind oxygen via a [[heme]] prosthetic group. They are widely distributed in many [[organism]]s.<ref name="pmid17540514">{{cite journal |vauthors=Vinogradov SN, Hoogewijs D, Bailly X, Mizuguchi K, Dewilde S, Moens L, Vanfleteren JR | title = A model of globin evolution | journal = Gene | volume = 398 | issue = 1–2 | pages = 132–42 |date=August 2007 | pmid = 17540514 | doi = 10.1016/j.gene.2007.02.041 }}</ref>

== Structure ==
Globin superfamily members share a common [[Tertiary structure|three-dimensional fold]].<ref>{{cite book|title=Introduction to protein structure|last2=Tooze|first2=John|date=1999|publisher=Garland Pub.|isbn=978-0815323051|edition=2nd|location=New York|last1=Branden|first1=Carl}}</ref> This 'globin fold' typically consists of eight [[Alpha helix|alpha helices]], although some proteins have additional helix extensions at their termini.<ref>{{Cite journal|last2=Onesti|first2=S|last3=Gatti|first3=G|last4=Coda|first4=A|last5=Ascenzi|first5=P|last6=Brunori|first6=M|year=1989|title=Aplysia limacina myoglobin. Crystallographic analysis at 1.6 a resolution|journal=Journal of Molecular Biology|volume=205|issue=3|pages=529–44|pmid=2926816|last1=Bolognesi|first1=M|doi=10.1016/0022-2836(89)90224-6}}</ref> Since the globin fold contains only helices, it is classified as an [[all-alpha protein fold]].

The globin fold is found in its namesake globin [[Protein families|families]] as well as in [[phycocyanin]]s. The globin fold was thus the first protein fold discovered (myoglobin was the first protein whose structure was solved).

=== Helix packaging ===
The eight helices of the globin fold core share significant nonlocal structure, unlike other [[structural motif]]s in which [[amino acid]]s close to each other in [[primary sequence]] are also close in space. The helices pack together at an average angle of about 50 degrees, significantly steeper than other helical packings such as the [[helix bundle]]. The exact angle of helix packing depends on the sequence of the protein, because packing is mediated by the [[steric]]s and [[hydrophobic]] interactions of the amino acid [[side chain]]s near the helix interfaces.

== Evolution ==
Globins [[evolution|evolved]] from a common ancestor and can be divided into three lineages:<ref name="pmid16061809">{{cite journal |last1=Vinogradov |first1=SN |last2=Hoogewijs |first2=D |last3=Bailly |first3=X |last4=Arredondo-Peter |first4=R |last5=Guertin |first5=M |last6=Gough |first6=J |last7=Dewilde |first7=S |last8=Moens |first8=L |last9=Vanfleteren |first9=JR |title=Three globin lineages belonging to two structural classes in genomes from the three kingdoms of life. |journal=Proceedings of the National Academy of Sciences of the United States of America |date=9 August 2005 |volume=102 |issue=32 |pages=11385–9 |doi=10.1073/pnas.0502103102 |pmid=16061809|pmc=1183549 |doi-access=free }}</ref><ref name=pmid23541529>{{cite journal |last1=Vinogradov |first1=Serge N. |last2=Tinajero-Trejo |first2=Mariana |last3=Poole |first3=Robert K. |last4=Hoogewijs |first4=David |title=Bacterial and archaeal globins — A revised perspective |journal=Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics |date=September 2013 |volume=1834 |issue=9 |pages=1789–1800 |doi=10.1016/j.bbapap.2013.03.021 |pmid=23541529|url=https://www.zora.uzh.ch/id/eprint/81249/1/Vingradov-Hoogewijs_BBA-Proteins_and_Proteomics_2013-main.pdf }}</ref>
* Family M (for myoglobin-like) or F (for FHb-like),<ref name="pmid32863222">{{cite journal |last1=Keppner |first1=A |last2=Maric |first2=D |last3=Correia |first3=M |last4=Koay |first4=TW |last5=Orlando |first5=IMC |last6=Vinogradov |first6=SN |last7=Hoogewijs |first7=D |title=Lessons from the post-genomic era: Globin diversity beyond oxygen binding and transport. |journal=Redox Biology |date=October 2020 |volume=37 |pages=101687 |doi=10.1016/j.redox.2020.101687 |pmid=32863222 |pmc=7475203}}</ref> which has a typical 3/3 fold.
** Subfamily FHb, for [[flavohaemoglobin]]s.  [[Fusion protein|Chimeric]].
** Subfamily SDgb, for single-domain globins (not to be confused with SSDgb).
* Family S (for sensor-like), again with a 3/3 fold.
** Subfamily GCS, for [[Globin-coupled sensor]]s. Chimeric.
** Subfamily PGb, for [[protoglobin]]s. Single-domain.
** Subfamily SSDgb, for sensor single-domain globins.
* Family T (for truncated), with a 2/2 fold<ref name="pmid26788940">{{cite journal |last1=Bustamante |first1=JP |last2=Radusky |first2=L |last3=Boechi |first3=L |last4=Estrin |first4=DA |last5=Ten Have |first5=A |last6=Martí |first6=MA |title=Evolutionary and Functional Relationships in the Truncated Hemoglobin Family. |journal=PLOS Computational Biology |date=January 2016 |volume=12 |issue=1 |pages=e1004701 |doi=10.1371/journal.pcbi.1004701 |pmid=26788940|pmc=4720485 |bibcode=2016PLSCB..12E4701B |doi-access=free }}</ref> All subfamilies can be chimeric, single-domain, or tandemly linked.<ref name="pmid32863222"/>
** Subfamily TrHb1 (also T1 or N).
** Subfamily TrHb2 (also T2 or O). Includes 2/2 [[phytoglobin]]s.
** Subfamily TrHb3 (also T3 or P).

The M/F family of globins is absent in [[archaea]]. Eukaryotes lack GCS, Pgb, and T3 subfamily globins.<ref name="pmid32863222"/>

Eight globins are known to occur in vertebrates: [[androglobin]] (Adgb), [[cytoglobin]] (Cygb), [[globin E]] (GbE, from bird eye), [[globin X]] (GbX, not found in mammals or birds), [[globin Y]] (GbY, from some mammals), [[hemoglobin]] (Hb), [[myoglobin]] (Mb) and [[neuroglobin]] (Ngb).<ref name="pmid32863222"/> All these types evolved from a single globin gene of F/M family<ref name="pmid32863222"/> found in basal animals.<ref>{{cite journal |last1=Burmester |first1=T |last2=Hankeln |first2=T |title=Function and evolution of vertebrate globins. |journal=Acta Physiologica |date=July 2014 |volume=211 |issue=3 |pages=501–14 |doi=10.1111/apha.12312 |pmid=24811692|s2cid=33770617 |doi-access=free }}</ref> The single gene has also invented an oxygen-carrying "hemoglobin" multiple times in other groups of animals.<ref>Solène Song, Viktor Starunov, Xavier Bailly, Christine Ruta, Pierre Kerner, Annemiek J.&nbsp;M. Cornelissen, Guillaume Balavoine: [https://bmcevolbiol.biomedcentral.com/articles/10.1186/s12862-020-01714-4 Globins in the marine annelid Platynereis dumerilii shed new light on hemoglobin evolution in bilaterians]. In: BMC Evolutionary Biology Vol.&nbsp;20, Issue&nbsp;165. 29 December 2020. [[doi:10.1186/s12862-020-01714-4]]. See also:
* [https://eurekalert.org/pub_releases/2020-12/c-asg122920.php A single gene 'invented' haemoglobin several times]. On: EurekAlert! 29 December 2020. Source: CNRS</ref> Several functionally different haemoglobins can coexist in the same [[species]].

=== Sequence conservation ===
Although the fold of the globin superfamily is highly [[evolution]]arily [[Conserved sequence|conserved]], the sequences that form the fold can have as low as 16% sequence identity. While the sequence specificity of the fold is not stringent, the [[hydrophobic core]] of the protein must be maintained and hydrophobic patches on the generally [[hydrophilic]] solvent-exposed surface must be avoided in order for the structure to remain stable and [[soluble]]. The most famous mutation in the globin fold is a change from [[glutamate]] to [[valine]] in one chain of the hemoglobin molecule. This mutation creates a "hydrophobic patch" on the protein surface that promotes intermolecular aggregation, the molecular event that gives rise to [[Sickle cell disease|sickle-cell disease]].{{Cn|date=November 2024}}

==Subfamilies==
*[[Leghaemoglobin]] {{InterPro|IPR001032}}
*[[Myoglobin]] {{InterPro|IPR002335}}
*[[Erythrocruorin]] {{InterPro|IPR002336}}
*[[HBB|Hemoglobin, beta]] {{InterPro|IPR002337}}
*[[HBA1|Hemoglobin, alpha]] {{InterPro|IPR002338}}
*[[Myoglobin, trematode type]] {{InterPro|IPR011406}}
*[[Globin, nematode]] {{InterPro|IPR012085}}
*[[Globin, lamprey/hagfish type]] {{InterPro|IPR013314}}
*[[Globin, annelid-type]] {{InterPro|IPR013316}}
*[[Haemoglobin, extracellular]] {{InterPro|IPR014610}}

== Examples ==

Human genes encoding globin proteins include:
* [[Cytoglobin|CYGB]]
* [[Hemoglobin, alpha 1|HBA1]], [[HBA2]], [[HBB]], [[HBD]], [[HBE1]], [[HBG1]], [[HBG2]], [[mu hemoglobin|HBM]], [[HBQ1]], [[Hemoglobin subunit zeta|HBZ]], [[myoglobin|MB]]

The globins include:

*[[Haemoglobin]] (Hb)
*[[Myoglobin]] (Mb)
* [[Neuroglobin]]: a myoglobin-like haemprotein [[gene expression|expressed]] in vertebrate [[brain]] and retina, where it is involved in neuroprotection from damage due to [[Hypoxia (medical)|hypoxia]] or [[ischemia]].<ref name="pmid12962627">{{cite journal |vauthors=Pesce A, Dewilde S, Nardini M, Moens L, Ascenzi P, Hankeln T, Burmester T, Bolognesi M | title = Human brain neuroglobin structure reveals a distinct mode of controlling oxygen affinity | journal = Structure | volume = 11 | issue = 9 | pages = 1087–95 |date=September 2003 | pmid = 12962627 | doi = 10.1016/S0969-2126(03)00166-7| doi-access = free | hdl = 10067/455310151162165141 | hdl-access = free }}</ref> Neuroglobin belongs to a branch of the globin family that diverged early in [[evolution]].
*[[Cytoglobin]]: an oxygen sensor [[Gene expression|expressed]] in multiple [[Biological tissue|tissues]]. Related to neuroglobin.<ref name="pmid15804833">{{cite journal |vauthors=Fago A, Hundahl C, Malte H, Weber RE | title = Functional properties of neuroglobin and cytoglobin. Insights into the ancestral physiological roles of globins | journal = IUBMB Life | volume = 56 | issue = 11–12 | pages = 689–96 | year = 2004 | pmid = 15804833 | doi = 10.1080/15216540500037299 | s2cid = 21182182 | doi-access = free }}</ref>
*[[Erythrocruorin]]: highly cooperative [[extracellular]] respiratory [[proteins]] found in [[annelid]]s and [[arthropod]]s that are assembled from as many as 180 subunit into hexagonal bilayers.<ref name="pmid17084861">{{cite journal |vauthors=Royer WE, Omartian MN, Knapp JE | title = Low resolution crystal structure of Arenicola erythrocruorin: influence of coiled coils on the architecture of a megadalton respiratory protein | journal = J. Mol. Biol. | volume = 365 | issue = 1 | pages = 226–36 |date=January 2007 | pmid = 17084861 | pmc = 1847385 | doi = 10.1016/j.jmb.2006.10.016 }}</ref>
*[[Leghaemoglobin]] (legHb or [[symbiosis|symbiotic]] Hb): occurs in the [[root nodule]]s of [[leguminous]] plants, where it facilitates the [[diffusion]] of oxygen to symbiotic bacteriods in order to promote [[nitrogen fixation]].
*[[Non-symbiotic haemoglobin]] (NsHb): occurs in non-leguminous plants, and can be over-expressed in stressed [[plants]] .
*[[Flavohaemoglobin]]s (FHb): chimeric, with an N-terminal globin domain and a C-terminal [[ferredoxin]] reductase-like NAD/FAD-binding domain. FHb provides protection against [[nitric oxide]] via its C-terminal domain, which transfers [[electron]]s to haem in the globin.<ref name="pmid11092893">{{cite journal |vauthors=Mukai M, Mills CE, Poole RK, Yeh SR | title = Flavohemoglobin, a globin with a peroxidase-like catalytic site | journal = J. Biol. Chem. | volume = 276 | issue = 10 | pages = 7272–7 |date=March 2001 | pmid = 11092893 | doi = 10.1074/jbc.M009280200 | doi-access = free }}</ref>
*Globin E: a globin responsible for storing and delivering oxygen to the retina in birds<ref>{{cite journal |vauthors=Blank M, Kiger L, Thielebein A, Gerlach F, Hankeln T, Marden MC, Burmeister T |title= Oxygen supply from the bird's eye perspective: Globin E is a respiratory protein in the chicken retina |journal= J. Biol. Chem. |volume=286|issue=30|pages=26507–15|year=2011|pmid=21622558|doi= 10.1074/jbc.M111.224634|url=https://www.sciencedaily.com/releases/2011/06/110623130749.htm |pmc=3143615|doi-access= free }}</ref>
*Globin-coupled sensors: chimeric, with an N-terminal myoglobin-like domain and a C-terminal domain that resembles the [[cytoplasm]]ic [[cell signalling|signalling]] domain of [[bacteria]]l chemoreceptors. They [[molecular binding|bind]] oxygen, and act to initiate an aerotactic response or [[Transcriptional regulation|regulate]] [[gene expression]].<ref name="pmid11481493">{{cite journal |vauthors=Hou S, Freitas T, Larsen RW, Piatibratov M, Sivozhelezov V, Yamamoto A, Meleshkevitch EA, Zimmer M, Ordal GW, Alam M | title = Globin-coupled sensors: a class of heme-containing sensors in Archaea and Bacteria | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 98 | issue = 16 | pages = 9353–8 |date=July 2001 | pmid = 11481493 | pmc = 55424 | doi = 10.1073/pnas.161185598 | bibcode = 2001PNAS...98.9353H | doi-access = free }}</ref><ref name="pmid15598488">{{cite journal |vauthors=Freitas TA, Saito JA, Hou S, Alam M | title = Globin-coupled sensors, protoglobins, and the last universal common ancestor | journal = J. Inorg. Biochem. | volume = 99 | issue = 1 | pages = 23–33 |date=January 2005 | pmid = 15598488 | doi = 10.1016/j.jinorgbio.2004.10.024 }}</ref>
*[[Protoglobin]]: a single domain globin found in [[archaea]] that is related to the N-terminal domain of globin-coupled sensors.<ref name="pmid15096613">{{cite journal |vauthors=Freitas TA, Hou S, Dioum EM, Saito JA, Newhouse J, Gonzalez G, Gilles-Gonzalez MA, Alam M | title = Ancestral hemoglobins in Archaea | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 101 | issue = 17 | pages = 6675–80 |date=April 2004 | pmid = 15096613 | pmc = 404104 | doi = 10.1073/pnas.0308657101 | bibcode = 2004PNAS..101.6675F | doi-access = free }}</ref>
*Truncated 2/2 globin: lack the first helix, giving them a 2-over-2 instead of the canonical 3-over-3 [[alpha helix|alpha-helical]] sandwich [[protein folding|fold]]. Can be divided into three main groups (I, II and II) based on [[secondary structure|structural]] features.
*HbN (or GlbN): a truncated haemoglobin-like protein that binds oxygen cooperatively with a very high affinity and a slow [[Dissociation (chemistry)|dissociation]] rate, which may exclude it from oxygen transport. It appears to be involved in [[bacterial]] nitric oxide [[detoxification]] and in nitrosative [[Stress (medicine)|stress]].<ref name="pmid16814781">{{cite journal |vauthors=Lama A, Pawaria S, Dikshit KL | title = Oxygen binding and NO scavenging properties of truncated hemoglobin, HbN, of Mycobacterium smegmatis | journal = FEBS Lett. | volume = 580 | issue = 17 | pages = 4031–41 |date=July 2006 | pmid = 16814781 | doi = 10.1016/j.febslet.2006.06.037 | doi-access = free }}</ref>
*[[Cyanoglobin]] (or GlbN): a truncated haemoprotein found in [[cyanobacteria]] that has high oxygen affinity, and which appears to serve as part of a terminal oxidase, rather than as a respiratory pigment.<ref name="pmid10684619">{{cite journal |vauthors=Yeh DC, Thorsteinsson MV, Bevan DR, Potts M, La Mar GN | title = Solution 1H NMR study of the heme cavity and folding topology of the abbreviated chain 118-residue globin from the cyanobacterium Nostoc commune | journal = Biochemistry | volume = 39 | issue = 6 | pages = 1389–99 |date=February 2000 | pmid = 10684619 | doi = 10.1021/bi992081l}}</ref>
*HbO (or GlbO): a truncated haemoglobin-like protein with a lower oxygen affinity than HbN. HbO associates with the bacterial [[cell (biology)|cell]] membrane, where it [[statistical significance|significantly]] increases oxygen uptake over [[Cell membrane|membrane]]s lacking this protein. HbO appears to [[protein–protein interaction|interact]] with a terminal oxidase, and could participate in an oxygen/electron-transfer process that facilitates oxygen transfer during [[aerobic metabolism]].<ref name="pmid11796724">{{cite journal |vauthors=Pathania R, Navani NK, Rajamohan G, Dikshit KL | title = Mycobacterium tuberculosis hemoglobin HbO associates with membranes and stimulates cellular respiration of recombinant Escherichia coli | journal = J. Biol. Chem. | volume = 277 | issue = 18 | pages = 15293–302 |date=May 2002 | pmid = 11796724 | doi = 10.1074/jbc.M111478200 | doi-access = free }}</ref>
*Glb3: a nuclear-encoded truncated haemoglobin from [[plant]]s that appears more closely related to HbO than HbN. Glb3 from ''[[Arabidopsis thaliana]]'' (Mouse-ear cress) exhibits an unusual concentration-independent binding of oxygen and [[carbon dioxide]].<ref name="pmid11526234">{{cite journal |vauthors=Watts RA, Hunt PW, Hvitved AN, Hargrove MS, Peacock WJ, Dennis ES | title = A hemoglobin from plants homologous to truncated hemoglobins of microorganisms | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 98 | issue = 18 | pages = 10119–24 |date=August 2001 | pmid = 11526234 | pmc = 56925 | doi = 10.1073/pnas.191349198 | bibcode = 2001PNAS...9810119W | doi-access = free }}</ref>

== The globin fold ==
The globin fold (cd01067) also includes some non-haem proteins. Some of them are the [[phycobiliprotein]]s, the N-terminal domain of [[two-component regulatory system]] [[histidine kinase]], ''RsbR'', and ''RsbN''.

==See also==
{{Portal|Biology}}
{{colbegin}}
*[[C-rich stability element]]
*[[Globular protein]]
*[[Hemoglobin]]
*[[Heme]]
*[[Myoglobin]]
*[[Phytoglobin]]
{{colend}}

==References==
{{reflist}}

{{Globins}}
{{InterPro content|IPR001486}}

[[Category:Protein superfamilies]]
[[Category:Protein folds]]