Editing Antibody (section)

== Structure ==
{{anchor|CDRs, Fv, Fab and Fc Regions}}
[[File:Antibody basic unit.svg|thumb|upright=1.2|right|Schematic structure of an antibody: two heavy chains (blue, yellow) and the two light chains (green, pink). The antigen binding site is circled.]]
{{multiple image
 | direction = vertical
 | footer = A more accurate depiction of an antibody (3D structure at [https://www.rcsb.org/3d-view/1IGY/1 RCSB PDB]). [[Glycans]] in the Fc region are shown in black.
 | image1 = Antibody IgG1 structure.png
 | alt1 = Model of an antibody showing beta strands
 | image2 = Antibody IgG1 surface.png
 | alt2 = Surface model of an antibody at the molecular level
}}
Antibodies are heavy (~150&nbsp;k[[Dalton (unit)|Da]]) [[protein]]s of about 10 [[Nanometre|nm]] in size,<ref>{{cite journal | vauthors = Reth M | title = Matching cellular dimensions with molecular sizes | journal = Nature Immunology | volume = 14 | issue = 8 | pages = 765–7 | date = August 2013 | pmid = 23867923 | doi = 10.1038/ni.2621 | s2cid = 24333875 | url = http://www.slas.ac.cn/upload/20130815-4.pdf | access-date = 1 May 2018 | archive-date = 2 May 2018 | archive-url = https://web.archive.org/web/20180502064449/http://www.slas.ac.cn/upload/20130815-4.pdf | url-status = dead }}</ref>
arranged in three [[globular protein|globular]] regions that roughly form a Y shape.

In humans and most other [[mammal]]s, an antibody unit consists of four [[polypeptide chain]]s; two identical ''[[Immunoglobulin heavy chain|heavy chains]]'' and two identical ''[[Immunoglobulin light chain|light chains]]'' connected by [[disulfide bond]]s.<ref name = woof/>
Each chain is a series of [[protein domain|domains]]: somewhat similar sequences of about 110 [[amino acid]]s each.
These domains are usually represented in simplified schematics as rectangles.
Light chains consist of one variable domain V<sub>L</sub> and one constant domain C<sub>L</sub>, while heavy chains contain one variable domain V<sub>H</sub> and three to four constant domains C<sub>H</sub>1, C<sub>H</sub>2, ...<ref>{{cite journal | vauthors = Barclay AN | title = Membrane proteins with immunoglobulin-like domains—a master superfamily of interaction molecules | journal = Seminars in Immunology | volume = 15 | issue = 4 | pages = 215–23 | date = August 2003 | pmid = 14690046 | doi = 10.1016/S1044-5323(03)00047-2 }}</ref>

Structurally an antibody is also partitioned into two [[Fragment antigen-binding|antigen-binding fragments]] (Fab), containing one V<sub>L</sub>, V<sub>H</sub>, C<sub>L</sub>, and C<sub>H</sub>1 domain each, as well as the [[Fragment crystallizable region|crystallisable fragment]] (Fc), forming the trunk of the Y shape.<ref name= putnam79>{{cite journal | vauthors = Putnam FW, Liu YS, Low TL | title = Primary structure of a human IgA1 immunoglobulin. IV. Streptococcal IgA1 protease, digestion, Fab and Fc fragments, and the complete amino acid sequence of the alpha 1 heavy chain | journal = The Journal of Biological Chemistry | volume = 254 | issue = 8 | pages = 2865–74 | date = April 1979 | doi = 10.1016/S0021-9258(17)30153-9 | pmid = 107164 | doi-access = free | bibcode = 1979JBiCh.254.2865P }}</ref>
In between them is a hinge region of the heavy chains, whose flexibility allows antibodies to bind to pairs of epitopes at various distances, to form complexes ([[protein dimer|dimer]]s, trimers, etc.), and to bind effector molecules more easily.<ref name="Roitt">{{Cite book | vauthors = Delves PJ, Martin SJ, Burton DR, Roitt IM |url=https://www.worldcat.org/oclc/949912256 |title=Roitt's essential immunology |date=2017 |isbn=978-1-118-41577-1 |edition=13th |location=Chichester, West Sussex |language=en |oclc=949912256}}</ref>

In an [[Serum protein electrophoresis|electrophoresis]] test of [[blood proteins]], antibodies mostly migrate to the last, [[gamma globulin]] fraction.
Conversely, most gamma-globulins are antibodies, which is why the two terms were historically used as synonyms, as were the symbols Ig and [[gamma|γ]].
This variant terminology fell out of use due to the correspondence being inexact and due to confusion with γ (gamma) [[Immunoglobulin heavy chain|heavy chains]] which characterize the [[IgG]] class of antibodies.<ref>{{Cite web |title=MeSH Browser – gamma-Globulins |url=https://meshb.nlm.nih.gov/record/ui?ui=D005719 |access-date=2020-10-18 |website=meshb.nlm.nih.gov}}</ref><ref>{{cite journal | title = Recommendations for the nomenclature of human immunoglobulins | journal = Journal of Immunology | volume = 108 | issue = 6 | pages = 1733–4 | date = June 1972 | doi = 10.4049/jimmunol.108.6.1733 | pmid = 5031329 | doi-access = free }}</ref>

===Antigen-binding site===
The variable domains can also be referred to as the F<sub>V</sub> region. It is the subregion of Fab that binds to an antigen.
More specifically, each variable domain contains three ''hypervariable regions'' – the amino acids seen there vary the most from antibody to antibody.
When the protein folds, these regions give rise to three loops of [[Beta sheet|β-strand]]s, localized near one another on the surface of the antibody.
These loops are referred to as the [[complementarity-determining region]]s (CDRs), since their shape complements that of an antigen.
Three CDRs from each of the heavy and light chains together form an antibody-binding site whose shape can be anything from a pocket to which a smaller antigen binds, to a larger surface, to a protrusion that sticks out into a groove in an antigen.
Typically though, only a few residues contribute to most of the binding energy.<ref name="Janeway5"/>

The existence of two identical antibody-binding sites allows antibody molecules to bind strongly to multivalent antigen (repeating sites such as [[polysaccharide]]s in [[bacterial cell wall]]s, or other sites at some distance apart), as well as to form antibody complexes and larger [[antigen-antibody complex]]es.<ref name="Janeway5"/>

The structures of CDRs have been clustered and classified by Chothia et al.<ref name= Chothia1997>
{{cite journal | vauthors = Al-Lazikani B, Lesk AM, Chothia C | title = Standard conformations for the canonical structures of immunoglobulins | journal = Journal of Molecular Biology | volume = 273 | issue = 4 | pages = 927–48 | date = November 1997 | pmid = 9367782 | doi = 10.1006/jmbi.1997.1354 }}</ref>
and more recently by North et al.<ref name= North2010>{{cite journal | vauthors = North B, Lehmann A, Dunbrack RL | title = A new clustering of antibody CDR loop conformations | journal = Journal of Molecular Biology | volume = 406 | issue = 2 | pages = 228–56 | date = February 2011 | pmid = 21035459 | pmc = 3065967 | doi = 10.1016/j.jmb.2010.10.030 }}</ref>
and Nikoloudis et al.<ref name= Nikoloudis2014>{{cite journal | vauthors = Nikoloudis D, Pitts JE, Saldanha JW | title = A complete, multi-level conformational clustering of antibody complementarity-determining regions | journal = PeerJ | volume = 2 | issue = e456 | pages = e456 | year = 2014 | pmid = 25071986 | pmc = 4103072 | doi = 10.7717/peerj.456 | doi-access = free }}</ref> However, describing an antibody's binding site using only one single static structure limits the understanding and characterization of the antibody's function and properties. To improve antibody structure prediction and to take the strongly correlated CDR loop and interface movements into account, antibody paratopes should be described as interconverting states in solution with varying probabilities.<ref name="Fernandez-Quintero2021">{{cite journal | vauthors = Fernández-Quintero ML, Georges G, Varga JM, Liedl KR | title = Ensembles in solution as a new paradigm for antibody structure prediction and design | journal = mAbs | volume = 13 | issue = 1 | pages = 1923122 | year = 2021 | pmid = 34030577 | pmc = 8158028 | doi = 10.1080/19420862.2021.1923122 }}</ref>

In the framework of the [[immune network theory]], CDRs are also called idiotypes. According to immune network theory, the adaptive immune system is regulated by interactions between idiotypes.<ref>{{cite web |title=Antibody Structure |url=https://www.bioatla.com/appendix/antibody-structure/#:~:text=These%20loops%20are%20referred%20to,regulated%20by%20interactions%20between%20idiotypes. |website=BioAtla | date=8 January 2016 |access-date=18 December 2024}}</ref>

===Fc region===
{{main|Fragment crystallizable region}}
The [[Fc region]] (the trunk of the Y shape) is composed of constant domains from the heavy chains. Its role is in modulating immune cell activity: it is where effector molecules bind to, triggering various effects after the antibody Fab region binds to an antigen.<ref name=Janeway5/><ref name=Roitt/>
[[Effector cell]]s (such as [[macrophage]]s or [[natural killer cell]]s) bind via their [[Fc receptor]]s (FcR) to the Fc region of an antibody, while the [[complement system]] is activated by binding the [[C1q]] protein complex. IgG or IgM can bind to C1q, but IgA cannot, therefore IgA does not activate the [[classical complement pathway]].<ref name="pmid21937984">{{cite journal | vauthors = Woof JM, Russell RW | title = Structure and function relationships in IgA | journal = [[Mucosal Immunology (journal)|Mucosal Immunology]] | volume = 4 | issue=6 | pages = 590–597 | date=2011 | doi = 10.1038/mi.2011.39 | pmid = 21937984| doi-access = free }}</ref>

Another role of the Fc region is to selectively distribute different antibody classes across the body. In particular, the [[neonatal Fc receptor]] (FcRn) binds to the Fc region of IgG antibodies to transport it across the placenta, from the mother to the fetus. In addition to this, binding to FcRn endows IgG with an exceptionally long half-life relative to other plasma proteins of 3-4 weeks. IgG3 in most cases (depending on allotype) has mutations at the FcRn binding site which lower affinity for FcRn, which are thought to have evolved to limit the highly inflammatory effects of this subclass.<ref>{{Cite journal |last1=Damelang |first1=Timon |last2=Rogerson |first2=Stephen J. |last3=Kent |first3=Stephen J. |last4=Chung |first4=Amy W. |date=March 2019 |title=Role of IgG3 in Infectious Diseases |url=https://doi.org/10.1016/j.it.2019.01.005 |journal=Trends in Immunology |volume=40 |issue=3 |pages=197–211 |doi=10.1016/j.it.2019.01.005 |pmid=30745265 |hdl=11343/284299 |s2cid=73419807 |issn=1471-4906|hdl-access=free }}</ref>

Antibodies are [[glycoprotein]]s,<ref name = "immune_glycan"/> that is, they have carbohydrates (glycans) added to conserved [[amino acid]] residues.<ref name = "immune_glycan"/><ref>{{cite journal | vauthors = Mattu TS, Pleass RJ, Willis AC, Kilian M, Wormald MR, Lellouch AC, Rudd PM, Woof JM, Dwek RA | title = The glycosylation and structure of human serum IgA1, Fab, and Fc regions and the role of N-glycosylation on Fcα receptor interactions | journal = The Journal of Biological Chemistry | volume = 273 | issue = 4 | pages = 2260–72 | date = January 1998 | pmid = 9442070 | doi = 10.1074/jbc.273.4.2260 | doi-access = free }}</ref>
These conserved [[glycosylation]] sites occur in the Fc region and influence interactions with effector molecules.<ref name = "immune_glycan">{{cite journal | vauthors = Maverakis E, Kim K, Shimoda M, Gershwin ME, Patel F, Wilken R, Raychaudhuri S, Ruhaak LR, Lebrilla CB | title = Glycans in the immune system and The Altered Glycan Theory of Autoimmunity: a critical review | journal = Journal of Autoimmunity | volume = 57 | issue = 6 | pages = 1–13 | date = February 2015 | pmid = 25578468 | pmc = 4340844 | doi = 10.1016/j.jaut.2014.12.002 }}</ref><ref>{{cite journal | vauthors = Cobb BA | title = The history of IgG glycosylation and where we are now | journal = Glycobiology | volume = 30 | issue = 4 | pages = 202–213 | date = March 2020 | pmid = 31504525 | pmc = 7109348 | doi = 10.1093/glycob/cwz065 }}</ref>

===Protein structure===
The [[N-terminus]] of each chain is situated at the tip.
Each [[immunoglobulin domain]] has a similar structure, characteristic of all the members of the [[immunoglobulin superfamily]]:
it is composed of between 7 (for constant domains) and 9 (for variable domains) [[β-strand]]s, forming two [[beta sheet]]s in a [[Beta sheet#Greek key motif|Greek key motif]].
The sheets create a "sandwich" shape, the [[immunoglobulin fold]], held together by a disulfide bond.<ref>{{Citation |title=Molecules, Cells, and Tissues of Immunity |date=2004-01-01 |work=Immunology Guidebook |pages=1–15 |editor-last=Cruse |editor-first=Julius M. |url=https://linkinghub.elsevier.com/retrieve/pii/B978012198382650025X |access-date=2025-02-15 |place=San Diego |publisher=Academic Press |doi=10.1016/b978-012198382-6/50025-x |isbn=978-0-12-198382-6 |editor2-last=Lewis |editor2-first=Robert E. |editor3-last=Wang |editor3-first=Huan }}</ref><ref>{{Citation |last=Bajorath |first=Jürgen |title=Cell Surface Receptors and Adhesion Molecules, Three-Dimensional Structures |date=1998-01-01 |encyclopedia=Encyclopedia of Immunology (Second Edition) |pages=515–520 |editor-last=Delves |editor-first=Peter J. |url=https://linkinghub.elsevier.com/retrieve/pii/B012226765600671X |access-date=2025-02-15 |place=Oxford |publisher=Elsevier |doi=10.1006/rwei.1999.0136 |isbn=978-0-12-226765-9}}</ref>

===Antibody complexes===
[[File:Mono-und-Polymere.svg|thumb|upright|Some antibodies form [[protein structure|complexes]] that bind to multiple antigen molecules.]]
Secreted antibodies can occur as a single Y-shaped unit, a [[monomer]].
However, some antibody classes also form [[protein dimer|dimers]] with two Ig units (as with IgA), [[tetramer protein|tetramer]]s with four Ig units (like [[teleost fish]] IgM), or [[pentamer]]s with five Ig units (like shark IgW or mammalian IgM, which occasionally forms [[hexamer]]s as well, with six units).<ref name = roux>{{cite journal | vauthors = Roux KH | title = Immunoglobulin structure and function as revealed by electron microscopy | journal = International Archives of Allergy and Immunology | volume = 120 | issue = 2 | pages = 85–99 | date = October 1999 | pmid = 10545762 | doi = 10.1159/000024226 | s2cid = 12187510 }}</ref> IgG can also form hexamers, though no J chain is required.<ref>{{Cite journal |last1=Diebolder |first1=Christoph A. |last2=Beurskens |first2=Frank J. |last3=de Jong |first3=Rob N. |last4=Koning |first4=Roman I. |last5=Strumane |first5=Kristin |last6=Lindorfer |first6=Margaret A. |last7=Voorhorst |first7=Marleen |last8=Ugurlar |first8=Deniz |last9=Rosati |first9=Sara |last10=Heck |first10=Albert J. R. |last11=van de Winkel |first11=Jan G. J. |last12=Wilson |first12=Ian A. |last13=Koster |first13=Abraham J. |last14=Taylor |first14=Ronald P. |last15=Ollmann Saphire |first15=Erica |date=2014-03-14 |title=Complement Is Activated by IgG Hexamers Assembled at the Cell Surface |journal=Science |language=en |volume=343 |issue=6176 |pages=1260–1263 |doi=10.1126/science.1248943 |issn=0036-8075 |pmc=4250092 |pmid=24626930|bibcode=2014Sci...343.1260D }}</ref> IgA tetramers and pentamers have also been reported.<ref>{{Cite journal |last1=Kumar |first1=Nikit |last2=Arthur |first2=Christopher P. |last3=Ciferri |first3=Claudio |last4=Matsumoto |first4=Marissa L. |date=2020-02-28 |title=Structure of the secretory immunoglobulin A core |url=https://www.science.org/doi/10.1126/science.aaz5807 |journal=Science |language=en |volume=367 |issue=6481 |pages=1008–1014 |doi=10.1126/science.aaz5807 |pmid=32029686 |bibcode=2020Sci...367.1008K |issn=0036-8075}}</ref>

Antibodies also form complexes by binding to antigen: this is called an [[antigen-antibody complex]] or ''immune complex''.
Small antigens can cross-link two antibodies, also leading to the formation of antibody dimers, trimers, tetramers, etc.
Multivalent antigens (e.g., cells with multiple epitopes) can form larger complexes with antibodies.
An extreme example is the clumping, or [[Hemagglutination|agglutination]], of [[red blood cell]]s with antibodies in [[blood typing]] to determine [[blood group]]s: the large clumps become insoluble, leading to visually apparent [[precipitation (chemistry)|precipitation]].<ref>{{cite book |last1=Actor |first1=Jeffrey K. |title=Elsevier's Integrated Review Immunology and Microbiology |date=2012 |publisher=Elsevier |isbn=978-0-323-07447-6 |page=71 |edition=2nd |chapter=Immunoassays |doi=10.1016/B978-0-323-07447-6.00009-0 |chapter-url=https://doi.org/10.1016/B978-0-323-07447-6.00009-0 |quote=Antibody-antigen interactions: the basis of quantitative and qualitative assays. Experimentally, if a known concentration of antibody is mixed with increasing amounts of specific antigen, then cross-linked antibody-antigen complexes begin to precipitate from the solution.}}</ref><ref>{{cite web |title=Immunology Laboratory: Hemagglutination |url=http://www.medicine.mcgill.ca/physio/vlab/immun/hemag.htm |website=medicine.mcgill.ca |publisher=The McGill Physiology Virtual Lab |author=<!--Not stated--> |access-date=2024-08-29}}</ref><ref>{{cite journal |last1=Yeow |first1=Natasha |last2=Tabor |first2=Rico F. |last3=Garnier |first3=Gil |title=Mapping the distribution of specific antibody interaction forces on individual red blood cells |journal=Scientific Reports |date=3 February 2017 |volume=7 |issue=1 |page=41956 |doi=10.1038/srep41956 |pmid=28157207 |pmc=5291206 |bibcode=2017NatSR...741956Y }}</ref>

===B cell receptors===
{{main|B-cell receptor}}
The membrane-bound form of an antibody may be called a ''surface immunoglobulin'' (sIg) or a ''membrane immunoglobulin'' (mIg). It is part of the ''B cell receptor'' (BCR), which allows a B cell to detect when a specific antigen is present in the body and triggers B cell activation.<ref name="T cell-dependent B cell activation">{{cite journal|vauthors=Parker DC|year=1993|title=T cell-dependent B cell activation|journal=Annual Review of Immunology|volume=11|issue=1|pages=331–60|doi=10.1146/annurev.iy.11.040193.001555|pmid=8476565}}</ref> The BCR is composed of surface-bound IgD or IgM antibodies and associated Ig-α and Ig-β [[heterodimer]]s, which are capable of [[signal transduction]].<ref name="Wintrobe">{{cite book | vauthors = Wintrobe MM |author-link= Maxwell Wintrobe| veditors = Greer JG, Foerster F, Lukens JN, Rodgers GM, Paraskevas F |title=Wintrobe's clinical hematology|edition=11|publisher=Lippincott Williams & Wilkins|location=Hagerstown, MD|year=2004|pages=453–456|isbn=978-0-7817-3650-3}}</ref> A typical human B cell will have 50,000 to 100,000 antibodies bound to its surface.<ref name="Wintrobe" /> Upon antigen binding, they cluster in large patches, which can exceed 1 micrometer in diameter, on lipid rafts that isolate the BCRs from most other [[cell signaling]] receptors.<ref name="Wintrobe" />
These patches may improve the efficiency of the [[Cell-mediated immunity|cellular immune response]].<ref name="pmid18275475">{{cite journal | vauthors = Tolar P, Sohn HW, Pierce SK | title = Viewing the antigen-induced initiation of B-cell activation in living cells | journal = Immunological Reviews | volume = 221 | issue = 1 | pages = 64–76 | date = February 2008 | pmid = 18275475 | doi = 10.1111/j.1600-065X.2008.00583.x | s2cid = 38464264 | url = https://zenodo.org/record/1230708 }}</ref> In humans, the cell surface is bare around the B cell receptors for several hundred nanometers,<ref name="Wintrobe"/> which further isolates the BCRs from competing influences.