Extracellular annexins in hemostasis system
Annexins are calcium-binding proteins that interact with cellular membranes due to their ability to bind phospholipids. The structural and functional peculiarities of these proteins have been described. Being cytosolic proteins, annexins also possess extracellular activities. However, there are some...
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| Cite this: | Extracellular annexins in hemostasis system / D.D. Zhernossekov, Y.M. Roka-Moiia, T.V. Grinenko // Вiopolymers and Cell. — 2016. — Т. 32, № 2. — С. 98-104. — Бібліогр.: 52 назв. — англ. |
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irk-123456789-1528162019-06-14T01:26:20Z Extracellular annexins in hemostasis system Zhernossekov, D.D. Roka-Moiia, Y.M. Grinenko, T.V. Reviews Annexins are calcium-binding proteins that interact with cellular membranes due to their ability to bind phospholipids. The structural and functional peculiarities of these proteins have been described. Being cytosolic proteins, annexins also possess extracellular activities. However, there are some controversial opinions concerning the functional role of extracellular annexins in the human hemostasis system. We have made an attempt to summarize the latest data and consider some ideas of possible annexin application in medical practice. Анексини – це кальцій-залежні протеїни, що взаємодіють з клітинними мембранами завдяки їх властивості зв’язувати фосфоліпіди. Структурно-функціональні особливості цих протеїнів надані в науковій літературі. Хоча анексини – цитозольні протеїни, для них притаманна позаклітинна активність. Існують суперечливі дані стосовно ролі позаклітинних анексинів у системі гемостазу. Ми спробували систематизувати сучасні наукові дані та виявити можливе застосування анексинів у медичній практиці. Аннексины – это кальций-зависимые протеины, взаимодействующие с клеточными мембранами благодаря их способности связывать фосфолипиды. Структурно-функциональные особенности этих белков описаны в научной литературе. Хотя аннексины – цитозольные протеины, для них показана внеклеточная активность. Существуют противоречивые мнения касательно функциональной роли внеклдеточных аннексинов в системе гемостаза. Мы предприняли попытку систематизировать последние научные данные и рассмотреть возможное применение аннексинов в медицинской практике. 2016 Article Extracellular annexins in hemostasis system / D.D. Zhernossekov, Y.M. Roka-Moiia, T.V. Grinenko // Вiopolymers and Cell. — 2016. — Т. 32, № 2. — С. 98-104. — Бібліогр.: 52 назв. — англ. 0233-7657 DOI: http://dx.doi.org/10.7124/bc.000911 http://dspace.nbuv.gov.ua/handle/123456789/152816 576. 522: 612.128 en Вiopolymers and Cell Інститут молекулярної біології і генетики НАН України |
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Annexins are calcium-binding proteins that interact with cellular membranes due to their ability to bind phospholipids. The structural and functional peculiarities of these proteins have been described. Being cytosolic proteins, annexins also possess extracellular activities. However, there are some controversial opinions concerning the functional role of extracellular annexins in the human hemostasis system. We have made an attempt to summarize the latest data and consider some ideas of possible annexin application in medical practice. |
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Zhernossekov, D.D. Roka-Moiia, Y.M. Grinenko, T.V. |
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Extracellular annexins in hemostasis system |
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Extracellular annexins in hemostasis system |
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Extracellular annexins in hemostasis system |
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Extracellular annexins in hemostasis system |
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Extracellular annexins in hemostasis system |
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extracellular annexins in hemostasis system |
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Extracellular annexins in hemostasis system / D.D. Zhernossekov, Y.M. Roka-Moiia, T.V. Grinenko // Вiopolymers and Cell. — 2016. — Т. 32, № 2. — С. 98-104. — Бібліогр.: 52 назв. — англ. |
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Вiopolymers and Cell |
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98
D. D. Zhernossekov, Y. M. Roka-Moiia, T. V. Grinenko
© 2016 D. D. Zhernossekov et al.; Published by the Institute of Molecular Biology and Genetics, NAS of Ukraine on behalf of Biopolymers and Cell.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/),
which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited
UDC 576. 522: 612.128
Extracellular annexins in hemostasis system
D. D. Zhernossekov, Y. M. Roka-Moiia, T. V. Grinenko
Palladin Institute of Biochemistry, NAS of Ukraine
9, Leontovycha Str., Kyiv, Ukraine, 01601
chemikdd@mail.ru
Annexins are calcium-binding proteins that interact with cellular membranes due to their ability to bind phos-
pholipids. The structural and functional peculiarities of these proteins have been described. Being cytosolic
proteins, annexins also possess extracellular activities. However, there are some controversial opinions con-
cerning the functional role of extracellular annexins in the human hemostasis system. We have made an at-
tempt to summarize the latest data and consider some ideas of possible annexin application in medical practice.
K e y w o r d s: annexins, hemostasis, plasminogen/plasmin system.
Annexins are considered as a family of calcium-de-
pendent phospholipid-binding proteins. The struc-
ture of these proteins has some common features [1]
(Fig.1). As a rule, annexins possess a variable ami-
no-terminal domain and a carboxyl core domain.
The last one is typically divided into four homolo-
gous domains (each of them is about 70 amino acid
residues) and each of these domains consists of five
α-helices. The amino-terminal domain contains sites
for posttranslational modification and protein-pro-
tein interaction. It has to be noted that this domain
provides the stability of the whole protein struc-
ture [2]. Posttranslational modifications in this re-
gion such as phosphorylation, acetylation or proteo-
lysis make influence on the structure of key regions
of the protein core even though they take place at the
opposite side of the annexin molecule. The carboxyl
core domain houses one or several calcium-binding
motives (KGXGT-38 residues-D/E). Apart from the
calcium-binding sites, in this domain there are also
the sites for binding to heparin, F-actin and phospho-
lipids (such as phosphatidyl serine and phosphati-
dylethanolamine). The annexins have been shown to
take part in many processes: exocytosis, endocyto-
sis, inhibition of blood coagulation, regulation of ion
transport across membranes, membrane reorganiza-
tion, vascular trafficking and redox regulation [3, 4].
In this review we mostly paid attention to those
members of annexin family that can be found in the
human hemostasis system. Normally annexins are
not secreted from the living cells, and the appear-
ance of these proteins in bloodstream can be con-
side red as a result of the cell degradation or apopto-
sis [5]. It is known that annexins lack the signal se-
quences that could direct them into the classical se-
cretory pathway. However, for annexins A1, A2 and
A5 the extracellular activity has been shown. Thus,
annexin A5 is considered as an anticoagulant pro-
tein, annexin A2 as an endothelial receptor for plas-
minogen and tissue plasminogen activator (tPA), and
annexin A1 as an anti-inflammatory agent [6].
Annexin A1 and its role in inflammation
Annexin A1 has the longest history of reported ex-
tracellular activity. It was found in human serum at
some pathological states such as myocardial infarc-
tion and experimental colitis [7,8]. The role of an-
nexin A1 in inflammation is related with glucocorti-
ISSN 1993-6842 (on-line); ISSN 0233-7657 (print)
Biopolymers and Cell. 2016. Vol. 32. N 2. P 98–104
doi: http://dx.doi.org/10.7124/bc.000911
mailto:chemikdd@mail.ru
99
Extracellular annexins in hemostasis system
coids as the main mechanism of glucocorticoids’
anti-inflammatory effects is an increase of the syn-
thesis and function of annexin A1 [9]. Glucocorticoids
bind to the cytosolic glucocorticoid receptor, a type
of nuclear receptor that is activated by the ligand
binding. After the hormone binds to the receptor, the
newly formed complex translocates itself into the
cell nucleus, where it binds to the glucocorticoid re-
sponse elements in the promoter region of annexin
A1 gene resulting in stimulation of the gene expres-
sion [10]. Annexin A1 inhibits phospholipase A2.
This is a calcium-dependent enzyme acting on phos-
pholipids of membranes that releases arachidonic
acid from the second carbon group of glycerol.
Arachidonic acid is a precursor of prostaglandins
and leucotriens playing the key role in the inflamma-
tory reactions. On the other hand, annexin A1 may
be considered as a regulator of leukocyte migration
[11, 12]. As it is known, there are specific A1 recep-
tors on the human neutrophils and monocytes [13].
They belong to the formyl peptide receptor (FRP)
family of chemoattractant receptors. FRPs are the
G-protein-coupled receptors, and they were identi-
fied by their ability to bind N-formyl peptides con-
taining an N-terminal N-formylmethionine produced
by the degradation of either bacterial or host cells
(they can be released by the mitochondria). The for-
myl peptide receptor (FPR) signaling pathways in-
clude the following steps: G-protein dependent acti-
vation of phospholipase C, activation of the regula-
tory small GTP-ase, and activation of CD38, ectoen-
zyme of the membrane surface. The final result of
the process is an increase in the cytoplasmic Ca2+
level. The sustained increase of calcium is required
for directed migration of the cells [14]. The sequenc-
es located in the unique N-terminal domain of an-
nexin A1 specifically interact with the formyl pep-
tide receptor on neutrophils, thereby eliciting the
receptor-mediated intracellular responses leading to
the inhibition of transendothelial migration.
Annexin A2 as a receptor on leukocytes and
endothelial cells
Annexin A2 found on the surface of endothelial cells
and leukocytes can function as a receptor for plas-
minogen and tPA acting as a positive modulator of
the fibrinolytic cascade. The increased expression of
annexin A2 on the surface of leukemic cells derived
from the acute promyelocytic leukemia patients cor-
relates with the clinical manifestation of blee-
ding [15].
Endothelial cells are thought to play a key role in
the intravascular plasmin generation, as they syn-
thetize and secrete plasminogen activators (tPA and
uPA) and their inhibitors (PAI-1) [16]. It is remark-
able that on endothelial cells, annexin A2 is consti-
tutively translocated to the cell surface within
16 hours of its biosynthesis where it may consist
5 % of the cellular protein pool [17]. Exogenous I125
–labeled annexin A2 bound to endothelial cell sur-
face with high affinity (Kd 49nM) in a calcium-de-
pendent manner. This binding may be blocked by
Fig. 1. Schematic representation of an-
nexin structure:
‒ calcium binding motive,
‒ binding protein,
‒ phosphate group.
100
D. D. Zhernossekov, Y. M. Roka-Moiia, T. V. Grinenko
peptides mimicking the classical “annexin repeat”
(KGXGT) [16].
Annexin A2 is thought to be a major membrane re-
ceptor of tPA on endothelium [18]. It has been shown
that tPA, plasminogen and plasmin bind to annexin
A2 through protein p11 with different affinity (Kd
0.68 µM, 0.11 µM and 75 nM respectively) [19].
There is a tight hydrophobic interaction between p11
and annexin A2. Complex p11-annexin A2 binds tPA,
plasmin and plasminogen due to the C-terminal lysine
residue of the p11 molecule [1]. The formed complex
can provide generation of the extracellular plasmin
(plasminogen is converted into plasmin by cleaving
peptide bond between Arg 561 and Val 562 by tPA)
[20]. However, the proposed profibrinolytic function
of annexin A2 is somewhat controversial, as there are
the data, that annexin A2 in complex with p11 can
also inhibit the plasmin activity and fibrinolysis [21].
Recently, it has been demonstrated that the tPA -
annexin A2 interaction may play a significant role
during inflammation process (Fig.2).
Under the stimulation of tPA, annexin A2 aggre-
gates with β-2 integrin CD 11b, leading to the activa-
tion of integrin-linked kinase (ILK) pathway [22].
Thus, annexin A2 can transduce tPA signaling
through its interaction with integrins. Annexin A2
mediates tPA-induced NF-kB activation in macro-
phages. In physiological status, the members of NF-
kB family (p50, p52, p65 and other) are retained in
the cytoplasm by the specific inhibitor IkB. Upon
activation, IkB becomes phosphorylated, which
leads to its degradation and the release of NF-kB di-
mers into nuclei. It results in the subsequent DNA
binding and transcription of the target proinflamma-
tory genes. Blocking any step of this cascade (e.g.
using annexin A2 antibodies) eliminates the tPA-in-
duced NF-kB activation.
Annexin A5 as an anticoagulant factor and
apoptosis marker
Annexin A5 was originally isolated from the human
umbilical cord artery by virtue of its anticoagulant ac-
Fig. 2. tPA-induced NF kB activation in
human macrophages: ann A2 – annexin
A2, Plg – plasminogen, Pm – plasmin,
tPA – tissue plasminogen activator, ILK –
integrin linked kinase, Pi – phosphate
group.
101
Extracellular annexins in hemostasis system
tivity [23]. As it was mentioned above, all calcium-
binding annexins are thought to be natural anticoagu-
lants. It is known that the phosphatidyl serine (PS)
exposure on the outer membrane is the characteristic
of the activated platelets or endothelial cells [24]. PS
facilitates the assembly and activation of the tenase
and prothrombinase complexes [25]. The annexin A5
binding to PS results in formation of an anticoagulant
shield on the cell membrane [5].This shield is of great
importance for placental cells as annexin A5 binds to
the apical surface of placental syncytiotrophoblasts
providing maintenance of normal blood flow through
the placenta. The disruption of the shield leads to the
development of antiphospholipid syndrome. As a re-
sult the apical surface of placenta becomes thrombo-
genic and patients with antiphospholipid syndrome
suffer from recurrent pregnancy losses [26]. It has
also been shown that extracellular as well as cytosolic
annexin A5 binds to the disrupted site of injured plas-
ma membrane as early as a few seconds after mem-
brane wounding and promotes membrane resealing
[27]. All these data raise the question of a role of an-
nexin A5 in the protection and repair of membrane
injuries in trophoblasts.
On the other hand, annexin A5 is the main annexin
of human platelets [28]. Annexin A5 binds to platelets
with high affinity (Kd 7nM) [29]. It was found that
each platelet has approximately 5,000 sites to bind an-
nexin A5. After thrombin stimulation, the amount of
annexin-binding sites per platelet can reach 200,000.
The treatment with phospholipase C or adding phos-
pholipase preparations to the platelet mixture led to
inhibition of annexin A5 binding [30]. Annexin A5 is
also exposed on the apoptotic platelets [31]. During
platelet apoptosis, the PS exposure occurs via the cas-
pase and calpain activation, when platelets undergo a
cellular death pathway leading to their clearance from
the circulation by scavenger cells [32]. These events
could be also induced in vitro by thrombin. It is re-
markable, that the aging and stored platelets were also
positive for PS [33]. However, it is necessary to carry
out the analysis of other biomarkers to distinguish the
platelet activation and apoptosis-mediated changes
from each other [34].
So, annexin A5 can serve as a marker of activated
or apoptotic platelets and its determination in blood
and on the surface of blood cells or endothelium can
be very important for the diagnosis and treatment of
hemostasis disorders [35].
Annexin A5 effect on plasminogen binding
In the presence of apoptotic factors, plasminogen
considerably increases phosphatidyl serine exposure.
This effect was shown for monocytes and neutro-
phils. The increased exposure of phosphatidyl serine
is associated with the growing plasminogen binding
to the cell surface [36]. This effect is explained by the
histone H2B exposure on the surface of apoptotic
monocytes. Histone H2B has different binding sites
for phosphatidyl serine and plasminogen and can
provide the efficient binding of both components
with the cell surface. Annexin A5 competes with his-
tone H2B for phosphatidyl serine binding and as a
result plasminogen binding to cells is inhibited.
On the other hand, the platelet activation with
thrombin led to an increased exposure of phosphati-
dyl serine in case of platelets and, as a result, eleva-
ted plasminogen binding was observed on the plate-
let surface [37]. The phosphatidyl serine exposure in
these experiments was detected using annexin A5. It
was found a special place on the platelet surface, so-
called protruding “cap”, where plasminogen [37],
thrombospondin and fibrinogen/fibrin were coloca-
lized [38]. As this “cap” was also the localization
place for factor XIIIa [39], it was suggested that fib-
rin plays a special role in amplifying the plasmino-
gen binding to annexin A5 bound platelets [37].
However, we could also observe the plasminogen
effect on the annexin A5 binding in case of activated
platelets [40]. In our experiments the exogenous
plasminogen preincubated with washed human
platelets leads to the increased exposure of annexin
A5 on the platelet surface after the thrombin stimula-
tion. As there are no data about the formation of an-
nexin A5-plasminogen complex, and histon H2b is
not exposed on the platelet surface, the mechanism
of the observed effect may be clarified only after se-
ries of further investigations.
102
D. D. Zhernossekov, Y. M. Roka-Moiia, T. V. Grinenko
Future perspective
Although numerous studies clearly indicate that ex-
tracellular annexins play an important role in the
functioning of human organisms, there are still many
gaps in our understanding of the molecular mecha-
nisms underlying their action. The structural pecu-
liarities of annexins may be very important in this
case. As it was shown some annexins (A2 and A5)
interact with carbohydrates, in particular glycosami-
noglycans. These interactions are likely to come into
play only for extracellular annexins but functional
significance of this binding remains to be proven
[41,42]. On the other hand, there are some proposals
for practical application of annexins in medical prac-
tice. It has been reported about diannexin, an annex-
in A5 homodimer that binds phosphatidyl serine
with high affinity (0.6 nM) [43]. This new prepara-
tion may find practical application in medicine due
to its ability to reduce the surface area coverage by
platelets perfused with human blood and to inhibit in
vivo the thrombus formation and fibrin deposition in
the rat and rabbit models of arterial and venous
thrombosis.
There are numerous reports about the agents con-
structed on the annexin base as apoptotic markers
[44-46]. Elevated annexin V levels have been found
in acute and chronic renal conditions [47]; in pa-
tients with heart failure a high circulating annexin
V level is likely to reflect peripheral organ damage
[48]. Some annexins can be predicted as therapeutic
agents. So, annexin V can be used in treatment of the
patients with sickle cell disease [49]. There are some
interesting reports concerning using annexin V as a
potential marker in tumors [50,51] and as a thera-
peutic agent for the patients with diffuse large B-cell
lymphoma [52].
However, future investigations are needed to clar-
ify the precise way of the annexin turnover in human
organism.
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Позаклітинні анексини у системі гемостазу
Д. Д. Жерносєков, Я. М. Рока-Мойя, T. В. Гриненко
Аннесини – це кальцій-залежні протеїни, що взаємодіють з
клітинними мембранами завдяки їх властивості зв’язувати
фосфоліпіди. Структурно-функціональні особливості цих про-
теїнів надані в науковій літературі. Хоча анексини – цитозольні
протеїни, для них притаманна позаклітинна активність.
Існують суперечливі дані стосовно ролі позаклітинних анекси-
нів у системі гемостазу. Ми спробували систематизувати су-
часні наукові дані та виявити можливе застосування анексинів
у медичній практиці.
К л юч ов і с л ов а: анексини, гемостаз, плазміноген/плазмі-
нова система.
Внеклеточние аннексины в системе гемостаза
Д. Д. Жерносеков, Я. М. Рока-Мойя, T. В. Гриненко
Аннексины – это кальций-зависимые протеины, которые взаи-
модействуют с клеточными мембранами благодаря их способ-
ности связывать фосфолипиды. Структурно-функциональные
особенности этих белков описаны в научной литературе. Хотя
аннексины – цитозольные протеины, для них показана внекле-
точная активность. Существуют противоречивые мнения каса-
тельно функциональной роли внеклеточних аннексинов в си-
стеме гемостаза. Мы предприняли попытку систематизировать
последние научные данные и рассмотреть возможное приме-
нение аннексинов в медицинской практике.
К л юч е в ы е с л ов а: аннексины, гемостаз, плазминоген/
плазминовая система.
Received 01.03.2016
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