In Keywords adaptor; anchor; docking protein; kinase; multidomain protein; phosphatase; protein interaction; scaffold; signaling; structural disorder Correspondence L.. Here we discuss t
Trang 1Functional classification of scaffold proteins and related molecules
La´szlo´ Buday1,2and Pe´ter Tompa1
1 Institute of Enzymology, Biological Research Center, Hungarian Academy of Sciences, Budapest, Hungary
2 Department of Medical Chemistry, Semmelweis University Medical School, Budapest, Hungary
Introduction
Cells use a multitude of signaling proteins to alter
cel-lular behavior in response to changes in their external
and internal environment Because of the multiplicity
and broad substrate specificity of signaling enzymes, it
is of immense importance to understand how the cell
achieves efficiency and accuracy in signaling It is
generally accepted that the primary mechanism is to
promote the proximity of signaling enzymes by specific binding to a special class of regulatory proteins [1–4] These proteins come under a variety of names, such as scaffold, adaptor, anchor and docking, but invariably function by ‘enforced proximity’, i.e by binding at least two signaling enzymes together and directing, coordinating and regulating their action (Fig 1) In
Keywords
adaptor; anchor; docking protein; kinase;
multidomain protein; phosphatase; protein
interaction; scaffold; signaling; structural
disorder
Correspondence
L Buday and P Tompa, Institute of
Enzymology, Hungarian Academy of
Sciences, 1518 Budapest, P.O Box 7,
Hungary
Fax: +361 466 5465
Tel: +361 279 3115; +361 279 3143
E-mail: buday@enzim.hu; tompa@enzim.hu
(Received 14 May 2010, revised 3 August
2010, accepted 18 August 2010)
doi:10.1111/j.1742-4658.2010.07864.x
In this series of four minireviews the field of scaffold proteins and proteins
of similar molecular⁄ cellular functions is overviewed By binding and bring-ing into proximity two or more signalbring-ing proteins, these proteins direct the flow of information in the cell by activating, coordinating and regulating signaling events in regulatory networks Here we discuss the categories of scaffolds, anchors, docking proteins and adaptors in some detail, and using many examples we demonstrate that they cover a wide range of functional modes that appear to segregate into three practical categories, simple pro-teins binding two partners together (adaptors), larger multidomain propro-teins targeting and regulating more proteins in complex ways (scaffold⁄ anchor-ing proteins) and proteins specialized to initiate signalanchor-ing cascades by local-izing partners at the cell membrane (docking proteins) It will also be shown, however, that the categories partially overlap and often their names are used interchangeably in the literature In addition, although not usually considered as scaffolds, several other proteins, such as regulatory proteins with catalytic activity, phosphatase targeting subunits, E3 ubiquitin ligases, ESCRT proteins in endosomal sorting and DNA damage sensors also func-tion by bona fide scaffolding mechanisms Thus, the field is in a state of continuous advance and expansion, which demands that the classification scheme be regularly updated and, if needed, revised
Abbreviations
AKAP, A-kinase anchoring protein; DAPP, dual-adapter for phosphotyrosine and 3-phosphoinositides; DD, death domain; FADD,
Fas-associated protein with death domain; MAGUK, membrane-associated guanylate kinase; MYPT1, myosin phosphatase targeting subunit 1; Nck, non-catalytic region of tyrosine kinase adaptor protein; PDZ, post-synaptic density, disc large, zo-1 protein; PH, pleckstrin homology; PSD, post-synaptic density; RTK, receptor tyrosine kinase; SH2, Src homology 2; SH3, Src homology 3; SKAP, Src kinase-associated phosphoprotein.
Trang 2the literature, the names are often used
interchange-ably, which indicates that the functions of the proteins
in the four categories overlap significantly and they are
often difficult to distinguished This article, and the
following three in this minireview series provide a
con-cise functional description of scaffold proteins and
their kin, in general, and their distinct classes, in
par-ticular, encompassing scaffolds [5], docking proteins
[6], anchors [7] and adaptors (this article)
We also point out overlaps and inconsistencies in
terminology, to show that members of this entire
functional class occupy positions along a rather
contin-uous functional spectrum We also describe targeting
subunits of phosphatases, which have a function in close analogy with that of anchors In addition, we also show that there are many other proteins that function using scaffolding mechanisms, and ought to
be considered in extending the classification scheme of these regulatory proteins It will be addressed that scaffold proteins and their kin not only bring signaling proteins together, but also regulate the flow of signal-ing information ussignal-ing a variety of mechanisms, owsignal-ing
to which proteins in this broad functional class no longer emerge as passive connectors, but active regula-tory elements shaping the response put out by signal-ing networks We suggest that this active role may also
be linked with extended structural disorder of the proteins [8–10], which enables dynamic communication between their distinct binding and functional elements (Fig 1 and Table 1)
It should also be made clear that because of space limitations this minireview is not comprehensive, and the reader is directed to many excellent recent reviews [1–4,11], and the other minireviews in this series [5–7] for further details and insight into this field of continu-ous advance
Scaffold/anchoring proteins Scaffold and anchoring proteins are reviewed in two of the other minireviews in this series [5,7] Here we pro-vide a short overview of their most notable examples,
to demonstrate that the distinction between these two categories is historical, rather than structural or functional
Scaffold proteins may be considered as the founders
of this functional class, epitomizing the very essence of the action of signaling regulatory proteins [5] They are defined as proteins organizing signaling complexes
by binding at least two signaling enzymes together and promoting their communication by proximity Classi-cally, they have been regarded as passive platforms for the assembly of signalosomes, but more recently it has become clear that they play rather active regulatory roles (Fig 1 and Table 1) They may operate by four basic mechanisms, such as enforced proximity, combi-natorial use of elements, dynamic regulation and con-formational fine-tuning [4,5] As demonstrated by one
of the best characterized scaffolds, Ste5, which regu-lates the extracellular signal-regulated kinase⁄ mitogen-activated protein kinase pathway in yeast, their func-tion may be to assemble complexes, enforce restricted intracellular localization, provide allosteric feedback and feed-forward regulation, and offer protection against degradation [3] They may enable context-dependent fine-tuning of pre-existing signaling
Adaptor A
Docking
P P P P
C
C
Scaffold/anchor B
Fig 1 Mechanisms of scaffold proteins and their kin This scheme
outlines the most important aspects of the function of modular
regu-latory proteins in the four (three) closely related categories In all
cat-egories, the proteins regulate signaling pathways by binding several
of the components and targeting ⁄ regulating their action in complex
ways (regulatory interactions ⁄ modifications marked by arrows).
Within this generalized scheme, there are three distinct types of
behavior (A) Adaptors are usually small, and have two binding
regions to target the action of two bound enzymes (B)
Scaf-folds ⁄ anchors are large multidomain proteins with a lot of structural
disorder, able to bind and regulate several members of a signaling
pathway (C) Docking proteins have a similar structural and functional
outline, their distinguishing feature being their ability to localize at
the membrane next to an activating receptor, to which they bind in a
phosphorylation-dependent manner In the entire class of proteins, a
high level of structural disorder (43.3% on average; Table 1) enables
key functional attributes, such as binding of several partners, to be
combined A, B and C marks general proteins P, phosphate.
Trang 3pathways or create new pathways using novel
combi-nations of signaling elements Scaffolds are extremely
heterogeneous in structure and function, which may
significantly overlap with those of other classes A few
selected examples (Table 1; cf [5]) show that they
often have separated binding domains for
protein–pro-tein interactions, and also have a high level of
struc-tural disorder, which may provide both short binding
regions and flexibility for dynamic regulatory
rear-rangements
These principles are also apparent in scaffolds that
operate in neuronal and immune cells, which are
highly polarized and form complex structures termed
synapses Synapses contain a plethora of receptors, ion
channels and signaling proteins for sensing and pro-cessing extracellular signals, organized and connected
to the cytoskeleton to form large complexes, such as the post-synaptic density (PSD) complex The best known of the scaffolds are the membrane-associated guanylate kinase (MAGUK) proteins, which have vari-ous numbers of post-synaptic density, disc large, zo-1 protein (PDZ) domains, an Src homology (SH)3 domain and a C-terminal guanylate kinase domain [1] The best studied MAGUK in T cells is DLG1, whereas in neurons it is PSD95, with notable similari-ties in function PSD95 is the most abundant scaffold
in the PSD, it has three PDZ domains, and binds
a variety of receptors⁄ channels, cytoskeletal and
Table 1 Scaffold proteins and their kin Representatives of the four categories of scaffold proteins and their relatives are presented The length of the human (unless indicated otherwise) isoform is given, along with its typical domains, binding partners and percent structural disorder, as predicted by the IUPred algorithm [42] Protein–protein interaction domains and interaction partners have been taken from the literature [1–7,22] and the list is not intended to be exhaustive AKAP, A-kinase anchoring protein; Caskin 1, CASK-interacting protein 1; DED, death effector domain; DLG(1), discs, large homolog (1); Dok1, docking protein 1; ERK, extracellular signal-regulated kinase; FADD, Fas-associated protein with death domain; FRS, FGF receptor substrate; Gab,Grb2-associated binder; Grb2, growth factor receptor-bound protein 2; IRS, insulin receptor substrate; KSR, kinase suppressor of Ras; MYPT1, myosin phosphatase targeting subunit 1; Nck1, non-cata-lytic region of tyrosine kinase adaptor protein 1; PDZ, post-synaptic density, disc large, zo-1 protein (domain); PH, pleckstrin homology domain; PI3-kinase, phosphoinositide-3-kinase; PKA, protein kinase A; PKC, protein kinase C; PP1, protein phosphatase 1; PSD, post-synaptic density; PTB, phosphotyrosine binding domain; RACK, receptor for activated C kinase; SARA, SMAD-anchor for receptor activation; SH2, Src homology 2 domain; SH3, Src homology 3 domain; Ste5, sterile 5; TGFb, transforming growth factor beta.
Protein
Length
(number of
Scaffold
Serpin
K+ channels, nNOS, NGL-2, SALM2, ADAM22, SYNGAP
95 (13.1)
Anchoring
Docking
Adaptor
SAM68, SLP-76, Sos, Synapsin, Vav
0 (0)
PAK, PRK2, Sos
48 (12.7)
Trang 4signaling proteins (Table 1) Because of its multiplicity
of binding partners, PSD95 functions in receptor
clustering, targeting receptor action on Ras and Rho
signaling, and regulating receptor modification
under-scoring dynamics of synaptic function A similar logic
applies to DLG1 (synapse-associated protein-97),
which regulates immunological synapses by physically
linking T-cell receptor signaling to cytoskeletal
rear-rangements Table 1 lists a few further scaffolds, all of
which are modular with several protein–protein
interaction domains and motifs embedded in and⁄ or
connected by long disordered regions, such as Shank1
and Caskin1 in neuronal PSD or SARA in
transform-ing growth factor beta signaltransform-ing
Scaffolds epitomize the very essence of the entire
family of signaling proteins, first appreciated in
tyro-sine kinase signaling where adaptors, scaffolds or
enzymes are recruited to the autophosphorylated
receptor tyrosine kinases (RTKs) Cytosolic kinases
and phosphatases, however, also require strict control
of their activity and subcellular localization, which is
achieved through anchoring proteins, originally defined
as proteins targeting the action of protein kinase A
(A-kinase anchoring proteins; AKAPs), on specific
substrates [7] They are usually long proteins with a lot
of structural disorder (Fig 1 and Table 1), with
func-tional attributes difficult to clearly distinguish from
that of scaffolds (described in detail in ref [7]) In
addition to AKAPs, protein kinase C also interacts
with a family of anchor proteins called receptors for
activated C kinase
Cytosolic Ser⁄ Thr phosphatases are also directed
into signaling networks by mechanisms similar to that
of protein kinase A and protein kinase C For
exam-ple, functional protein phosphatase 1 consists of a
cat-alytic subunit and a regulatory subunit The regulatory
subunits target the catalytic subunit to specific cellular
compartments and modulate substrate specificity [12]
One of the best characterized regulatory subunits is the
myosin phosphatase target subunit (MYPT1) A
num-ber of regulatory proteins, as well as Ser⁄ Thr kinases,
can associate with MYPT1, suggesting that similarly
to AKAPs and receptors for activated C kinase, the
function of MYPT1 is much broader than simply
tar-geting protein phosphatase 1 to myosin II [13]
Docking proteins
As outlined in the accompanying minireview by
Brum-mer et al [6], docking proteins were originally defined
as accessory proteins in RTK signaling with a
mem-brane-targeting region, a protein–protein interaction
site for receptor binding and an extended region with
several Tyr residues for receptor-dependent phosphory-lation (Fig 1 and Table 1) This outline applies to all four major families of classical docking protein, such
as the Grb2-associated binder⁄ daughter of sevenless (Gab⁄ DOS), insulin receptor substrate, FGF receptor substrate and docking protein families [6] Docking proteins are recruited to the site of RTK activation at the plasma membrane, they reinforce binding by virtue
of a receptor-binding domain (often a phosphotyro-sine-binding domain) and undergo multiple Tyr-phos-phorylation (there are more than five Tyr phosphorylation sites in at least one of the family members) Phosphorylation of Tyr residues is rather specific to certain RTKs, but may also proceed by cytoplasmic tyrosine kinases Tyr-phosphorylated docking proteins recruit SH2-domain-containing sig-naling components to initiate specific signal cascades, and they coordinate and regulate Tyr kinase signaling events, and also display dynamic regulatory phenom-ena described in more detail for scaffold proteins (for details see ref [6])
There are also other, atypical docking proteins [6], which lack the lipid-binding domain but have N-termi-nal domains⁄ regions that help them localize at the plasma membrane next to activating receptors, and also contain several Tyr residues that undergo phos-phorylation and recruitment of signaling proteins Although the function of these proteins (linker for activated T cells, Crk-associated substrate, SLP65) is closely related to other docking proteins, they appear
to be better classified as scaffolds
Adaptor proteins The term adaptor protein is generally used for low molecular mass molecules that serve to link two func-tional members of a catalytic pathway (Fig 1 and Table 1) Adaptors either possess two domains involved
in protein–protein interactions or use two regions com-posed of two to three domains The first group of adap-tor proteins identified was the family of SH2⁄ SH3 domain-containing proteins, including growth factor receptor-bound protein 2, Crk, CrkL and non-catalytic region of tyrosine kinase adaptor protein 1 (Nck) [14] Their SH2 domain binds specific phosphotyrosine resi-dues on activated receptors or their substrates, whereas their SH3 domains bind proline-rich motifs on down-stream target proteins Interestingly, this family of adaptor proteins contains only one SH2 domain, whereas they usually possess two or more SH3 domains In theory, more than one SH3 domains may allow the adaptor to recruit several ligands separately; however, it seems from earlier studies that cooperation
Trang 5exists between the SH3 domains for ligand binding For
example, Nck adaptor contains one SH2 domain and
three SH3 domains Although individual SH3 domains
of Nck were reported to be able to bind partners, such
as p21 protein (Cdc42⁄ Rac)-activated kinase or PRK2,
experimental data clearly showed that Nck constructs
containing all three SH3 domains bind the protein
part-ners with much higher affinity than the single SH3
domains [15,16] Therefore, it is highly likely that even
those adaptors which contain two or three tandem SH3
domains actually link only two members of a catalytic
pathway
SH2⁄ SH3 domain-containing adaptors link
down-stream target molecules to the membrane-bound
recep-tor In some cases, the adaptor may recruit binding
partners directly to the plasma membrane through its
lipid-binding domain In hematopoietic cells, pleckstrin
homology domain (PH)-containing adaptor molecules
provide important links between
phosphoinositide-3 kinase and lymphocyte function For example,
recruitment of Src kinase-associated phosphoprotein
(SKAP) and B-lymphocyte adapter molecule of 32 kDa
(Bam32)⁄ dual-adapter for phosphotyrosine and
3-phos-phoinositides (DAPP) to the plasma membrane of
acti-vated lymphocytes is driven by lipid products generated
through the action of phosphoinositide-3 kinase [17]
Whereas SKAP contains a PH domain on the
N-termi-nus and an SH3 domain on the C-termiN-termi-nus, Bam32⁄
DAPP1 possesses an SH2 domain and a PH domain
Therefore, although both adaptors could bind
phospho-inositide in the plasma membrane, SKAP recruits
pro-line-rich target molecules, whereas Bam32⁄ DAPP1 may
associate with phosphotyrosine-containing proteins
Possessing a PH domain for membrane association, this
subfamily of adaptors, including SKAP, Bam32 and
SH2B proteins, performs a bona fide adaptor function,
they nevertheless link downstream targets directly to
the plasma membrane DAPP [17]
The majority of adaptor molecules are implicated in
RTK signaling, however, other cell-surface receptors
also utilize adaptors possessing specific modular
domains Death receptors, members of the tumor
necrosis factor receptor superfamily, possess a
cytoplas-mic death domain (DD) They transmit signals through
apical protein complexes, which are nucleated by the
death domain adaptors Fas-associated protein with
death domain (FADD) and tumor necrosis factor
receptor type 1-associated death domain protein
(TRADD) FADD is a protein containing two
structur-ally similar protein motifs, the N-terminal death
effec-tor domain and the C-terminal DD The primary role
of FADD in death receptor signaling is to recruit
initia-tor procaspase 8 and procaspase 10 to death recepinitia-tors
[18] The principle by which the SH2⁄ SH3 domain-con-taining adaptors and FADD function is very similar, and the modular domains of growth factor receptor-bound protein 2 and FADD are commutable This was demonstrated by creating an artificial signaling pathway
in which the SH2 domain of growth factor receptor-bound protein 2 was fused to the death effector domain
of FADD The chimeric adaptor protein could reroute RTK signals to induce procaspase activation and cell death [19]
Classification of scaffolds and its limitations
The functions of the above four closely related catego-ries of signaling regulatory proteins show significant similarities and overlap (Fig 1 and Table 1), but appear to segregate into three broad functional catego-ries: simple proteins binding two partners together (adaptors), larger multidomain proteins targeting and regulating more proteins in complex ways (scaf-folds⁄ anchoring proteins) and proteins specialized to initiate signaling cascades by localizing partners at the cell membrane (docking proteins)
This classification has both advantages and limita-tions Its major advantage is simplification, because it enables one to think in terms of a few concepts instead
of a practically unmanageable number of individual observations This very fact, however, also makes it inherently limited, because of the necessary neglect of many details If such exceptions to the ‘rule’ of the system become too numerous, the system has to be improved⁄ refined to comply with progress in the field Here we list a few such notable exceptions that may eventually demand the extension of the classification scheme
A diagnostic mark of the limitations inherent in the scheme is that very often the names are used inter-changeably, without much attempt to clarify where the given protein belongs to For example, anchoring pro-teins are often also termed scaffolds [4,7], the term scaf-folds and adaptors are sometimes used interchangeably [1,4], the distinction between docking and adaptor is somewhat arbitrary [6], and docking proteins may also
be termed adaptors and scaffolds [2] There are many individual proteins called by different names in differ-ent articles, such as MyD88 scaffold and adaptor [3], linker for activated T cells (LAT) scaffold [3] and dock-ing protein [6], GAB dockdock-ing protein [6] and scaffold [4], mAKAP anchor protein [7] and scaffold [4],
MAG-UK proteins, which ‘anchor’ receptors at the synapse, scaffold [1] and adaptor [20], FGF receptor substrate docking protein [6] and ‘scaffold adaptor’ [21] These
Trang 6and many other examples in the literature demonstrate
that the terms cannot be unequivocally separated
A different type of limitation is the exclusion of
pro-teins with enzymatic activity Although it serves the
simple purpose of separating two basic functions in
signal transduction – enzymes that act and proteins
that orchestrate their action [22] – it is clear that it
cannot be done for many relevant proteins that have
both enzymatic domains and regulatory
protein–pro-tein interaction domains In effect, there are several
proteins considered as scaffolds that have enzymatic
activity, such as MAGUK proteins already discussed
among scaffolds [3], RNAse E [23], MEKK1 of the
JNK signaling pathway [24], RTKs themselves [3] or
integrin-linked kinase [25] Actually, there is little
func-tional distinction between a scaffold protein binding a
given enzyme partner and a scaffold that has an
enzy-matic domain of the same type
An additional complicating factor is that there are
many other signaling pathways beyond kinase cascades,
which are rather neglected in this context For example,
transfer of the small protein ubiquitin proceeds via a
cascade, from E1 ubiquitin-activating enzyme to E2
ubiquitin-conjugating enzyme to a specific substrate
with the intervention of a targeting-type of interaction
mediated by E3 ubiquitin ligases Because ubiquitinated
target proteins may be targeted for degradation or
sig-naling activation [26], the operation of E3 proteins,
such as MDM2 [27] and Siah-2 [28], can be best
ratio-nalized by the scaffold concept The assembly of
Esc-herichia coli RNA degradosome by RNAse E [23] is
also of very similar molecular logic It has been
sug-gested that there are also adaptors that are important in
pathways activated by internal signals, such as DNA
damage, e.g MDC1 in DNA doule-strand breaks [20]
and BRCA1 in many cellular pathways including DNA
repair [29] In a similar vein, trafficking of signaling
proteins is itself dependent on adaptors associated with
protein sorting in endosomes, such as ESCRT [30] In
addition, both proteins and also metabolites can be
scaffolded, as demonstrated by Pmel17, a physiological
amyloid that ‘scaffolds’ and ‘sequesters’ toxic
interme-diates during the biosynthesis of the pigment melanin in
melanocytes in the skin [31]
Of further note, many fully or largely disordered
pro-teins noted for their assembly function (see below) are
not usually considered to be scaffold proteins, although
they do bind and orchestrate the action of several
sig-naling partners, such as caldesmon (Ca2+⁄ calmodulin,
F-actin, myosin, tropomyosin), SIBLING proteins
(integrin, complement factor H, CD44, fibronectin), or
RNAPII CTD (capping, splicing and polyadenylation
factors) The molecular mechanism and function of
these proteins also comply with the scaffolding princi-ples outlined in this article
Scaffold proteins and structural disorder
The decision on what is included among scaffolds can also be approached from a structural point of view, because in all categories – with the possible exception of adaptors – the proteins have a very high level of func-tion-related structural disorder (Table 1) It has recently been recognized that a significant proportion of eukary-otic genomes encodes for proteins (IDPs) or regions of proteins (IDRs) that lack a well-defined 3D structure under native, functional conditions [10,32–34] Struc-tural disorder abounds in proteins of regulatory and sig-naling function, and it is also closely correlated with disease, such as cancer and neurodegenerative disorders The molecular function of IDPs⁄ IDRs may stem either from recognition of partner molecules via short motifs [35,36] or disordered domains [37], from regulatory post-translational modification and also from providing
‘entropic-chain’ functions, such as linkers and segments contributing entropic exclusion and force generation
As a result, the molecular function of scaffolds corre-sponds to the ‘assembler’ function of IDPs, i.e they have been described to assemble complexes [9,34,37] The role of structural disorder in scaffold-type func-tions is also apparent in hub proteins, which have been found to have a large number of binding partners in high-throughput studies of protein–protein interactions
in the interactome [38] In particular, ‘party’ hubs have been defined as those being able to bind their partners simultaneously, which is the very essence of the action
of scaffolds Hub proteins have an elevated level of dis-order [39], which is also the case with the examples cited here (average disorder, 43.3%; Table 1), and also previ-ous findings that scaffold proteins constitute one of the most disordered functional categories [8,40] and the average disorder correlates with the number of subunits
of multiprotein complexes [41] In all, structural disor-der seems to be closely associated with several attributes
of scaffold function, such as the ability of binding multi-ple partners, mediating their commulti-plex and transient interactions and themselves undergoing a complex array
of regulatory post-translational modifications (Fig 1)
Conclusion: where is the field of scaffolds headed?
From all the considerations described, it seems that a useful practical functional classification of scaffold proteins and their kin can be given At first sight, all
Trang 7the proteins enlisted represent variations on a common
theme, binding signaling proteins together to direct
and control the flow of information in the cell This
basic theme segregates in a rather consistent manner
into three coherent categories Scaffold⁄ anchor
pro-teins usually bind more than two signaling components
together and regulate their activity in complex and
dynamic ways, involving activation and repression of
activity Adaptor proteins are usually smaller and their
function is simpler, connecting two partners together
Docking proteins distinguish themselves by assembling
signaling complexes at the plasma membrane in a
Tyr-phosphorylation-dependent way There are many
pro-teins excluded from this scheme, although they do act
via very closely related mechanisms Their inclusion
following careful judgment of their functional modes,
possibly leading to an extension of the classification
scheme, should be considered
Acknowledgements
This work is supported by grants OTKA K60694 and
NK71582 from the Hungarian Scientific Research
Fund and ETT 245⁄ 2006 from the Hungarian Ministry
of Health (for PT), the Miha´ly Pola´nyi Program
(Agency for Research Fund Management and
Research Exploitation, KPI) and a ‘Lendu¨let’ grant
from the Hungarian Academy of Sciences (for LB)
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