Integrin: Integrin Alphavbeta3 Extracellular Domains

Integrin
Integrin alphaVbeta3
extracellular domains
Structure of the extracellular segment

of integrin alpha Vbeta3.[1]
Identifiers
Symbol Integrin_alphaVbeta3
Pfam PF08441 (http://pfa
m.xfam.org/family?ac
c=PF08441)
Pfam clan CL0159 (http://pfam.x
fam.org/clan/CL0159)
InterPro IPR013649 (https://w
ww.ebi.ac.uk/interpro/
entry/IPR013649)
SCOPe 1jv2 (https://scop.ber
keley.edu/search/key
=1jv2) / SUPFAM (htt
p://supfam.org/SUPE
RFAMILY/cgi-bin/sear
ch.cgi?search_field=1
jv2)
OPM 176 (https://opm.pha
superfamily r.umich.edu/protein_s
uperfamilies/176)
OPM protein 2knc (https://opm.pha
r.umich.edu/proteins?
search=2knc)
Membranome 13 (http://membrano
me.org/protein_super
families/13)
Available protein structures:
Pfam structures (http://pfam.xfam.or

g/family/PF08441?tab=pdbBlo
ck) / ECOD (http://prodata.swm
ed.edu/ecod/complete/searc
h?kw=PF08441)
PDB RCSB PDB (http://www.rcsb.or

g/pdb/search/smartSubquery.d
o?smartSearchSubtype=PfamI
dQuery&pfamID=PF08441);
PDBe (https://www.ebi.ac.uk/p
dbe/entry/search/index?pfam_
accession:PF08441); PDBj (htt
ps://pdbj.org/searchFor?query
=PF08441)
PDBsum structure summary (https://ww

w.ebi.ac.uk/thornton-srv/datab
ases/cgi-bin/pdbsum/GetPfam
Str.pl?pfam_id=PF08441)
Integrin alpha cytoplasmic

region
Structure of chaperone protein

PAPD.[2]
Identifiers
Symbol Integrin_alpha
Pfam PF00357 (http://pfam.xfa
m.org/family?acc=PF0035
7)
InterPro IPR000413 (https://www.e
bi.ac.uk/interpro/entry/IPR
000413)
PROSITE PDOC00215 (http://www.e
xpasy.org/cgi-bin/prosite-s
earch-ac?PDOC00215)
SCOPe 1dpk (https://scop.berkele
y.edu/search/key=1dpk) /
SUPFAM (http://supfam.or
g/SUPERFAMILY/cgi-bin/s
earch.cgi?search_field=1d
pk)

h?kw=PF00357)

=PF00357)

Integrin, beta chain (vWA)
Identifiers
Symbol Integrin_beta
Pfam PF00362 (http://pfam.xfa
m.org/family?acc=PF0036
2)
InterPro IPR002369 (https://www.e
bi.ac.uk/interpro/entry/IPR
002369)
SMART SM00187 (http://smart.em
bl-heidelberg.de/smart/do
_annotation.pl?DOMAIN=
SM00187)
PROSITE PDOC00216 (http://www.e
xpasy.org/cgi-bin/prosite-s
earch-ac?PDOC00216)
SCOPe 1jv2 (https://scop.berkeley.
edu/search/key=1jv2) /
g/SUPERFAMILY/cgi-bin/s
earch.cgi?search_field=1jv
2)

h?kw=PF00362)

=PF00362)

PDB 1jv2 (https://www.rcsb.org/struc

ture/1jv2), 1kup (https://www.rc
sb.org/structure/1kup), 1kuz (ht
tps://www.rcsb.org/structure/1k
uz), 1l3y (https://www.rcsb.org/
structure/1l3y), 1l5g (https://ww
w.rcsb.org/structure/1l5g),
1m1x (https://www.rcsb.org/str
ucture/1m1x), 1m8o (https://w
ww.rcsb.org/structure/1m8o),
1s4x (https://www.rcsb.org/stru
cture/1s4x), 1txv (https://www.r
csb.org/structure/1txv), 1ty3 (ht
tps://www.rcsb.org/structure/1ty
3), 1ty5 (https://www.rcsb.org/st
ructure/1ty5), 1ty6 (https://ww
w.rcsb.org/structure/1ty6), 1ty7
(https://www.rcsb.org/structure/
1ty7), 1tye (https://www.rcsb.or
g/structure/1tye), 1u8c (https://
www.rcsb.org/structure/1u8c)
Integrin beta 7 cytoplasmic

domain: complex with
filamin
crystal structure of the filamin a
repeat 21 complexed with the integrin
beta7 cytoplasmic tail peptide
Identifiers
Symbol Integrin_b_cyt
Pfam PF08725 (http://pfam.xfam.
org/family?acc=PF08725)
InterPro IPR014836 (https://www.eb
i.ac.uk/interpro/entry/IPR01
4836)
SCOPe 1m8O (https://scop.berkele
y.edu/search/key=1m8O) /
g/SUPERFAMILY/cgi-bin/se
arch.cgi?search_field=1m8
O)

h?kw=PF08725)

=PF08725)

Integrins are transmembrane receptors that facilitate cell-extracellular matrix (ECM) adhesion. Upon ligand
binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the
cell cycle, organization of the intracellular cytoskeleton, and movement of new receptors to the cell
membrane.[3] The presence of integrins allows rapid and flexible responses to events at the cell surface (e.g.
signal platelets to initiate an interaction with coagulation factors).
Several types of integrins exist, and one cell may have multiple different types on its surface. Integrins are
found in all animals while integrin-like receptors are found in plant cells.[4]
Integrins work alongside other proteins such as cadherins, the immunoglobulin superfamily cell adhesion
molecules, selectins and syndecans, to mediate cell–cell and cell–matrix interaction. Ligands for integrins
include fibronectin, vitronectin, collagen and laminin.
Contents
Structure
Structure
Activation
Function
Attachment of cell to the ECM
Signal transduction
Integrins and nerve repair
Vertebrate integrins
References
External links
Structure
Integrins are obligate heterodimers, meaning that they have two subunits: α (alpha) and β (beta). Integrins in
mammals have eighteen α and eight β subunits,[5] in Drosophila five α and two β subunits, and in
Caenorhabditis nematodes two α subunits and one β subunit.[6] The α and β subunits each penetrate the
plasma membrane and possess several cytoplasmic domains.[7]
alpha (mammal)
gene protein synonyms
ITGA1 (https://www.genenames.org/tools/search/#!/genes?query=ITGA1) CD49a VLA1
ITGA2 (https://www.genenames.org/tools/search/#!/genes?query=ITGA2) CD49b VLA2
ITGA3 (https://www.genenames.org/tools/search/#!/genes?query=ITGA3) CD49c VLA3
ITGA4 (https://www.genenames.org/tools/search/#!/genes?query=ITGA4) CD49d VLA4
ITGA5 (https://www.genenames.org/tools/search/#!/genes?query=ITGA5) CD49e VLA5
ITGA6 (https://www.genenames.org/tools/search/#!/genes?query=ITGA6) CD49f VLA6
ITGA7 (https://www.genenames.org/tools/search/#!/genes?query=ITGA7) ITGA7 FLJ25220
ITGA8 (https://www.genenames.org/tools/search/#!/genes?query=ITGA8) ITGA8
ITGA9 (https://www.genenames.org/tools/search/#!/genes?query=ITGA9) ITGA9 RLC
ITGA10 (https://www.genenames.org/tools/search/#!/genes?query=ITGA10) ITGA10 PRO827
ITGA11 (https://www.genenames.org/tools/search/#!/genes?query=ITGA11) ITGA11 HsT18964
ITGAD (https://www.genenames.org/tools/search/#!/genes?query=ITGAD) CD11D FLJ39841
ITGAE (https://www.genenames.org/tools/search/#!/genes?query=ITGAE) CD103 HUMINAE
ITGAL (https://www.genenames.org/tools/search/#!/genes?query=ITGAL) CD11a LFA1A
ITGAM (https://www.genenames.org/tools/search/#!/genes?query=ITGAM) CD11b MAC-1
ITGAV (https://www.genenames.org/tools/search/#!/genes?query=ITGAV) CD51 VNRA, MSK8
ITGA2B (https://www.genenames.org/tools/search/#!/genes?query=ITGA2B) CD41 GPIIb
ITGAX (https://www.genenames.org/tools/search/#!/genes?query=ITGAX) CD11c
beta (mammal)
gene protein synonyms
ITGB1 (https://www.genenames.org/tools/search/#!/genes?query=ITGB1) CD29 FNRB, MSK12, MDF2
ITGB2 (https://www.genenames.org/tools/search/#!/genes?query=ITGB2) CD18 LFA-1, MAC-1, MFI7
ITGB3 (https://www.genenames.org/tools/search/#!/genes?query=ITGB3) CD61 GP3A, GPIIIa
ITGB4 (https://www.genenames.org/tools/search/#!/genes?query=ITGB4) CD104
ITGB5 (https://www.genenames.org/tools/search/#!/genes?query=ITGB5) ITGB5 FLJ26658
ITGB6 (https://www.genenames.org/tools/search/#!/genes?query=ITGB6) ITGB6
Variants of some subunits are formed by differential RNA splicing; for example, four variants of the beta-1
subunit exist. Through different combinations of the α and β subunits, around 24 unique integrins are
generated.[8]
Integrin subunits span the cell membrane and have short cytoplasmic domains of 40–70 amino acids. The
exception is the beta-4 subunit, which has a cytoplasmic domain of 1,088 amino acids, one of the largest of
any membrane protein. Outside the cell membrane, the α and β chains lie close together along a length of
about 23 nm; the final 5 nm N-termini of each chain forms a ligand-binding region for the ECM. They have
been compared to lobster claws, although they don't actually "pinch" their ligand, they chemically interact with
it at the insides of the "tips" of their "pinchers".
The molecular mass of the integrin subunits can vary from 90 kDa to 160 kDa. Beta subunits have four
cysteine-rich repeated sequences. Both α and β subunits bind several divalent cations. The role of divalent
cations in the α subunit is unknown, but may stabilize the folds of the protein. The cations in the β subunits are
more interesting: they are directly involved in coordinating at least some of the ligands that integrins bind.
Integrins can be categorized in multiple ways. For example, some α chains have an additional structural
element (or "domain") inserted toward the N-terminal, the alpha-A domain (so called because it has a similar
structure to the A-domains found in the protein von Willebrand factor; it is also termed the α-I domain).
Integrins carrying this domain either bind to collagens (e.g. integrins α1 β1, and α2 β1), or act as cell-cell
adhesion molecules (integrins of the β2 family). This α-I domain is the binding site for ligands of such
integrins. Those integrins that don't carry this inserted domain also have an A-domain in their ligand binding
site, but this A-domain is found on the β subunit.
In both cases, the A-domains carry up to three divalent cation binding sites. One is permanently occupied in
physiological concentrations of divalent cations, and carries either a calcium or magnesium ion, the principal
divalent cations in blood at median concentrations of 1.4 mM (calcium) and 0.8 mM (magnesium). The other
two sites become occupied by cations when ligands bind—at least for those ligands involving an acidic amino
acid in their interaction sites. An acidic amino acid features in the integrin-interaction site of many ECM
proteins, for example as part of the amino acid sequence Arginine-Glycine-Aspartic acid ("RGD" in the one-
letter amino acid code).
Structure
Despite many years of effort, discovering the high-resolution structure of integrins proved to be challenging, as
membrane proteins are classically difficult to purify, and as integrins are large, complex and linked to many
sugar trees ("highly glycosylated"). Low-resolution images of detergent extracts of intact integrin GPIIbIIIa,
obtained using electron microscopy, and even data from indirect techniques that investigate the solution
properties of integrins using ultracentrifugation and light scattering, were combined with fragmentary high-
resolution crystallographic or NMR data from single or paired domains of single integrin chains, and molecular
models postulated for the rest of the chains.
The X-ray crystal structure obtained for the complete extracellular region of one integrin, αvβ3,[1] shows the
molecule to be folded into an inverted V-shape that potentially brings the ligand-binding sites close to the cell
membrane. Perhaps more importantly, the crystal structure was also obtained for the same integrin bound to a
small ligand containing the RGD-sequence, the drug cilengitide.[9] As detailed above, this finally revealed
why divalent cations (in the A-domains) are critical for RGD-ligand binding to integrins. The interaction of
such sequences with integrins is believed to be a primary switch by which ECM exerts its effects on cell
behaviour.
The structure poses many questions, especially regarding ligand binding and signal transduction. The ligand
binding site is directed towards the C-terminal of the integrin, the region where the molecule emerges from the
cell membrane. If it emerges orthogonally from the membrane, the ligand binding site would apparently be
obstructed, especially as integrin ligands are typically massive and well cross-linked components of the ECM.
In fact, little is known about the angle that membrane proteins subtend to the plane of the membrane; this is a
problem difficult to address with available technologies. The default assumption is that they emerge rather like
little lollipops, but the evidence for this sweet supposition is noticeable by its absence. The integrin structure
has drawn attention to this problem, which may have general implications for how membrane proteins work. It
appears that the integrin transmembrane helices are tilted (see "Activation" below), which hints that the
extracellular chains may also not be orthogonal with respect to the membrane surface.
Although the crystal structure changed surprisingly little after binding to cilengitide, the current hypothesis is
that integrin function involves changes in shape to move the ligand-binding site into a more accessible
position, away from the cell surface, and this shape change also triggers intracellular signaling. There is a wide
body of cell-biological and biochemical literature that supports this view. Perhaps the most convincing
evidence involves the use of antibodies that only recognize integrins when they have bound to their ligands, or
are activated. As the "footprint" that an antibody makes on its binding target is roughly a circle about 3 nm in
diameter, the resolution of this technique is low. Nevertheless, these so-called LIBS (Ligand-Induced-Binding-
Sites) antibodies unequivocally show that dramatic changes in integrin shape routinely occur. However, how
the changes detected with antibodies look on the structure is still unknown.
Activation
When released into the cell membrane, newly synthesized integrin dimers are speculated to be found in the
same "bent" conformation revealed by the structural studies described above. One school of thought claims
that this bent form prevents them from interacting with their ligands, although bent forms can predominate in
high-resolution EM structures of integrin bound to an ECM ligand. Therefore, at least in biochemical
experiments, integrin dimers must apparently not be 'unbent' in order to prime them and allow their binding to
the ECM. In cells, the priming is accomplished by a protein talin, which binds to the β tail of the integrin dimer
and changes its conformation.[10][11] The α and β integrin chains are both class-I transmembrane proteins: they
pass the plasma membrane as single transmembrane alpha-helices. Unfortunately, the helices are too long, and
recent studies suggest that, for integrin gpIIbIIIa, they are tilted with respect both to one another and to the
plane of the membrane. Talin binding alters the angle of tilt of the β3 chain transmembrane helix in model
systems and this may reflect a stage in the process of inside-out signalling which primes integrins.[12]
Moreover, talin proteins are able to dimerize[13] and thus are thought to intervene in the clustering of integrin
dimers which leads to the formation of a focal adhesion. Recently, the Kindlin-1 and Kindlin-2 proteins have
also been found to interact with integrin and activate it.[14]
Function
Integrins have two main functions, attachment of the cells to the ECM and signal transduction from the ECM
to the cells.[15] They are also involved in a wide range of other biological activities, including extravasation,
cell-to-cell adhesion, cell migration, and as receptors for certain viruses, such as adenovirus, echovirus,
hantavirus, and foot-and-mouth disease, polio virus and other viruses.
A prominent function of the integrins is seen in the molecule GpIIb/IIIa, an integrin on the surface of blood
platelets (thrombocytes) responsible for attachment to fibrin within a developing blood clot. This molecule
dramatically increases its binding affinity for fibrin/fibrinogen through association of platelets with exposed
collagens in the wound site. Upon association of platelets with collagen, GPIIb/IIIa changes shape, allowing it
to bind to fibrin and other blood components to form the clot matrix and stop blood loss.
Attachment of cell to the ECM
Integrins couple the ECM outside a cell to the cytoskeleton (in particular, the microfilaments) inside the cell.
Which ligand in the ECM the integrin can bind to is defined by which α and β subunits the integrin is made of.
Among the ligands of integrins are fibronectin, vitronectin, collagen, and laminin. The connection between the
cell and the ECM may help the cell to endure pulling forces without being ripped out of the ECM. The ability
of a cell to create this kind of bond is also of vital importance in ontogeny.
Cell attachment to the ECM is a basic requirement to build a multicellular organism. Integrins are not simply
hooks, but give the cell critical signals about the nature of its surroundings. Together with signals arising from
receptors for soluble growth factors like VEGF, EGF, and many others, they enforce a cellular decision on
what biological action to take, be it attachment, movement, death, or differentiation. Thus integrins lie at the
heart of many cellular biological processes. The attachment of the cell takes place through formation of cell
adhesion complexes, which consist of integrins and many cytoplasmic proteins, such as talin, vinculin,
paxillin, and alpha-actinin. These act by regulating kinases such as FAK (focal adhesion kinase) and Src
kinase family members to phosphorylate substrates such as p130CAS thereby recruiting signaling adaptors
such as CRK. These adhesion complexes attach to the actin cytoskeleton. The integrins thus serve to link two
networks across the plasma membrane: the extracellular ECM and the intracellular actin filamentous system.
Integrin α6β4 is an exception: it links to the keratin intermediate filament system in epithelial cells.[16]
Focal adhesions are large molecular complexes, which are generated following interaction of integrins with
ECM, then their clustering. The clusters likely provide sufficient intracellular binding sites to permit the
formation of stable signaling complexes on the cytoplasmic side of the cell membrane. So the focal adhesions
contain integrin ligand, integrin molecule, and associate plaque proteins. Binding is propelled by changes in
free energy.[17] As previously stated, these complexes connect the extracellular matrix to actin bundles. Cryo-
electron tomography reveals that the adhesion contains particles on the cell membrane with diameter of 25 +/-
5 nm and spaced at approximately 45 nm.[18] Treatment with Rho-kinase inhibitor Y-27632 reduces the size of
the particle, and it is extremely mechanosensitive.[19]
One important function of integrins on cells in tissue culture is their role in cell migration. Cells adhere to a
substrate through their integrins. During movement, the cell makes new attachments to the substrate at its front
and concurrently releases those at its rear. When released from the substrate, integrin molecules are taken back
into the cell by endocytosis; they are transported through the cell to its front by the endocytic cycle, where they
are added back to the surface. In this way they are cycled for reuse, enabling the cell to make fresh attachments
at its leading front.[20] The cycle of integrin endocytosis and recycling back to the cell surface is important also
for not migrating cells and during animal development.[21]
Signal transduction
Integrins play an important role in cell signaling by modulating the cell signaling pathways of transmembrane
protein kinases such as receptor tyrosine kinases (RTK). While the interaction between integrin and receptor
tyrosine kinases originally was thought of as uni-directional and supportive, recent studies indicate that
integrins have additional, multi-faceted roles in cell signaling. Integrins can regulate the receptor tyrosine
kinase signaling by recruiting specific adaptors to the plasma membrane. For example, β1c integrin recruits
Gab1/Shp2 and presents Shp2 to IGF1R, resulting in dephosphorylation of the receptor.[22] In a reverse
direction, when a receptor tyrosine kinase is activated, integrins co-localise at focal adhesion with the receptor
tyrosine kinases and their associated signaling molecules.
The repertoire of integrins expressed on a particular cell can specify the signaling pathway due to the
differential binding affinity of ECM ligands for the integrins. The tissue stiffness and matrix composition can
initiate specific signaling pathways regulating cell behavior. Clustering and activation of the integrins/actin
complexes strengthen the focal adhesion interaction and initiate the framework for cell signaling through
assembly of adhesomes.[23]
Depending on the integrin's regulatory impact on specific receptor tyrosine kinases, the cell can experience:
cell growth,
cell division,
cell survival,
cellular differentiation, and
apoptosis (programmed cell death).
Knowledge of the relationship between integrins and receptor tyrosine kinase has laid a foundation for new
approaches to cancer therapy. Specifically, targeting integrins associated with RTKs is an emerging approach
for inhibiting angiogenesis.[24]
Integrins and nerve repair

Integrins have an important function in neuroregeneration after injury
of the peripheral nervous system (PNS).[25] Integrins are present at
the growth cone of damaged PNS neurons and attach to ligands in the
ECM to promote axon regeneration. It is unclear whether integrins
can promote axon regeneration in the adult central nervous system
(CNS). There are two obstacles that prevent integrin-mediated
regeneration in the CNS: 1) integrins are not localised in the axon of
most adult CNS neurons and 2) integrins become inactivated by
molecules in the scar tissue after injury.[25]
Vertebrate integrins Integrins are localised at the growth

cone of regenerating neurons.[25]
The following are 16 of the ~24 integrins found in vertebrates:
Name Synonyms Distribution Ligands
α1β1 VLA-1 Many Collagens, laminins[26]
α2β1 VLA-2 Many Collagens, laminins[26]
α3β1 VLA-3 Many Laminin-5
α4β1 VLA-4[26] Hematopoietic cells Fibronectin, VCAM-1[26]

VLA-5; fibronectin
α5β1 widespread fibronectin[26] and proteinases
receptor
VLA-6; laminin
α6β1 widespread laminins
receptor
α7β1 muscle, glioma laminins
αL β2 LFA-1[26] T-lymphocytes ICAM-1, ICAM-2[26]

αMβ2 Mac-1, CR3[26] Neutrophils and monocytes Serum proteins, ICAM-1[26]
Fibrinogen
αIIb β3 receptor; Platelets[26] fibrinogen, fibronectin[26]
gpIIbIIIa[27]
ocular melanoma; neurological
αVβ1 vitronectin; fibrinogen
tumors
vitronectin activated endothelial cells, vitronectin,[28] fibronectin, fibrinogen, osteopontin,

αVβ3
receptor[28] melanoma, glioblastoma Cyr61, thyroxine,[29] TETRAC
widespread, esp. fibroblasts,
αVβ5 vitronectin and adenovirus
epithelial cells
proliferating epithelia, esp. lung
αVβ6 fibronectin; TGFβ1+3
and mammary gland
αVβ8 neural tissue; peripheral nerve fibronectin; TGFβ1+3
α6β4 Epithelial cells[26] Laminin[26]
Beta-1 integrins interact with many alpha integrin chains. Gene knockouts of integrins in mice are not always
lethal, which suggests that during embryonal development, one integrin may substitute its function for another
in order to allow survival. Some integrins are on the cell surface in an inactive state, and can be rapidly primed,
or put into a state capable of binding their ligands, by cytokines. Integrins can assume several different well-
defined shapes or "conformational states". Once primed, the conformational state changes to stimulate ligand
binding, which then activates the receptors — also by inducing a shape change — to trigger outside-in signal
transduction.
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External links
Media related to Integrins at Wikimedia Commons
Talin substrate for calpain (https://www.youtube.com/watch?v=8DOTnKHFTTg) – PMAP The

Proteolysis Map animation.
Integrins (https://meshb.nlm.nih.gov/record/ui?name=Integrins) at the US National Library of
Medicine Medical Subject Headings (MeSH)
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Integrin: Integrin Alphavbeta3 Extracellular Domains

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Integrin

Structure of the extracellular segment

Pfam structures (http://pfam.xfam.or

PDB RCSB PDB (http://www.rcsb.or

PDBsum structure summary (https://ww

Integrin alpha cytoplasmic

Structure of chaperone protein

Pfam structures (http://pfam.xfam.or

PDB RCSB PDB (http://www.rcsb.or

PDBsum structure summary (https://ww

Integrin, beta chain (vWA)

Pfam structures (http://pfam.xfam.or

PDB RCSB PDB (http://www.rcsb.or

PDBsum structure summary (https://ww

PDB 1jv2 (https://www.rcsb.org/struc

Integrin beta 7 cytoplasmic

Pfam structures (http://pfam.xfam.or

PDB RCSB PDB (http://www.rcsb.or

PDBsum structure summary (https://ww

Attachment of cell to the ECM

Integrins and nerve repair

Vertebrate integrins Integrins are localised at the growth

α4β1 VLA-4[26] Hematopoietic cells Fibronectin, VCAM-1[26]

αL β2 LFA-1[26] T-lymphocytes ICAM-1, ICAM-2[26]

vitronectin activated endothelial cells, vitronectin,[28] fibronectin, fibrinogen, osteopontin,

α6β4 Epithelial cells[26] Laminin[26]

Talin substrate for calpain (https://www.youtube.com/watch?v=8DOTnKHFTTg) – PMAP The

Retrieved from "https://en.wikipedia.org/w/index.php?title=Integrin&oldid=969504491"

This page was last edited on 25 July 2020, at 20:55 (UTC).

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