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RNA-binding protein

From Wikipedia, the free encyclopedia
RNA-binding proteins (often abbreviated as RBPs) are proteins that bind to the double or
single stranded RN
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in cells and participate in forming ribonucleoprotein comple$es% RBPs
contain RN recognition motifs (RR&s)% 'hey are cytoplasmic and nuclear proteins%
(o)ever, since most mature RN is e$ported from the nucleus relatively *uickly, most RBPs
in the nucleus e$ist as comple$es of protein and pre+mRN called heterogeneous
ribonucleoprotein particles(hnRNPs)% RBPs have crucial roles in various cellular processes
such as, cellular function, transport and locali-ation% 'hey especially play a ma.or role in
post+ transcriptional control of RNs, such as, splicing, polyadenylation, mRN stabili-ation,
mRN locali-ation and translation% /ukaryotic cells encode diverse RBPs, appro$imately 011
genes, )ith uni*ue RN+binding activity and protein+protein interaction% 2uring evolution, the
diversity of RBPs greatly increased )ith the increase in the number of introns% 2iversity
enabled eukaryotic cells to utili-e RN e$ons in various arrangements, giving rise to a
uni*ue RNP (ribonucleoprotein) for each RN% lthough RBPs have a crucial role in post+
transcriptional regulation in gene e$pression, relatively fe) RBPs have been studied
systematically%
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Contents
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• " 5tructure
• 3 2iversity
• 4 Function
o 4%" RN processing and modification
 4%"%" lternative splicing
 4%"%3 RN editing
 4%"%4 Polyadenylation
o 4%3 /$port
o 4%4 mRN locali-ation
o 4%6 'ranslation
• 6 RN+binding activity and recognition of the RN se*uence
o 6%" RN+recognition motif (RR&)
o 6%3 2ouble+stranded RN+binding motif (dsRB&)
o 6%4 7inc fingers
• 0 Role in embryonic development
o 0%" RBPs in germline development
o 0%3 RBPs in somatic development
o 0%4 RBPs in neuronal development
• 8 9urrent research
• : 5ee also
• ; /$ternal links
• < References
Structure[edit]
&any RBPs have modular structures and are composed of multiple repeats of .ust a fe)
specific basic domains that often have limited se*uences% 'hese se*uences are then
arranged in varying combinations to fulfill the need for diversity% specific protein=s
recognition of a specific RN has evolved through the rearrangement of these fe) basic
domains% /ach basic domain recogni-es RN, but many of these proteins re*uire multiple
copies of one of the many common domains to function%
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Diversity[edit]
s nuclear RN emerges from RN polymerase, RN transcripts are immediately covered
)ith RN+binding proteins that regulate every aspect of RN metabolism and function
including RN biogenesis, maturation, transport, cellular locali-ation and stability% ll RBPs
bind RN, ho)ever they do so )ith different RN+se*uence specificities and affinities, )hich
allo)s the RBPs to be as diverse as their targets and functions%
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'hese targets
include mRN, )hich codes for proteins, as )ell as a number of functional non+coding
RNs% NcRNs almost al)ays function as ribonucleoprotein comple$es and not as naked
RNs% 'hese non+coding RNs includemicroRNs, small interfering RNs (siRN), as )ell
as splicesomal small nuclear RNs (snRN)%
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Function[edit]
RNA processing and modification[edit]
Alternative splicing[edit]
lternative splicing is a mechanism by )hich different forms of mature mRNs (messengers
RNs) are generated from the same gene% >t is a regulatory mechanism by )hich variations
in the incorporation of the e$ons into mRN leads to the production of more than one related
protein, thus e$panding possible genomic outputs% RBPs function e$tensively in the
regulation of this process% 5ome binding proteins such as neuronal specific RN+binding
proteins, namely N?@, control the alternative splicing of a subset of hnRN by recogni-ing
and binding to a specific se*uence in the RN (A9A )here A indicates pyrimidine, B or 9)%
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'hese proteins then recruit splicesomal proteins to this target site% 5R proteins are also
)ell kno)n for their role in alternative splicing through the recruitment of snRNPsthat form
the splicesome, namely B" snRNP and B3F snRNP% (o)ever, RBPs are also part of the
splicesome itself% 'he splicesome is a comple$ of snRN and protein subunits and acts as
the mechanical agent that removes introns and ligates the flanking e$ons%
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RNA editing[edit]
ADAR , an RN binding protein involved in RN editing events%
'he most e$tensively studied form of RN editing involves the 2R protein% 'his protein
functions through post+transcriptional modification of mRN transcripts by changing
the nucleotide content of the RN% 'his is done through the conversion
of adenosine to inosine in an en-ymatic reaction cataly-ed by 2R% 'his process
effectively changes the RN se*uence from that encoded by the genome and e$tends the
diversity of the gene products% 'he ma.ority of RN editing occurs on non+coding regions of
RNC ho)ever, some protein+encoding RN transcripts have been sho)n to be sub.ect to
editing resulting in a difference in their proteinDs amino acid se*uence% n e$ample of this is
the glutamate receptor mRN )here glutamine is converted to arginine leading to a change
in the functionality of the protein%
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Polyadenylation[edit]
Polyadenylation is the addition of a EtailF of adenylate residues to an RN transcript about 31
bases do)nstream of the B se*uence )ithin the three prime untranslated region%
Polyadenylation of mRN has a strong effect on its nuclear transport, translation efficiency,
and stability% ll of these as )ell as the process of polyadenylation depend on binding of
specific RBPs% ll eukaryotic mRNs )ith fe) e$ceptions are processed to receive 4D poly
() tails of about 311 nucleotides% ?ne of the necessary protein comple$es in this process
is 9P5F% 9P5F binds to the 4D tail (B) se*uence and together )ith another protein
called poly()+binding protein, recruits and stimulates the activity of poly() polymerase%
Poly() polymerase is inactive on its o)n and re*uires the binding of these other proteins to
function properly%
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Export[edit]
fter processing is complete, mRN needs to be transported from the
cell nucleus to cytoplasm% 'his is a three step process involving the generation of a cargo+
carrier comple$ in the nucleus follo)ed by translocation of the comple$ through the nuclear
pore comple$ and finally release of the cargo into cytoplasm% 'he carrier is then
subse*uently recycled% 'PGNHF",p"0 heterodimer is thought to be the key player in mRN
e$port% ?ver+e$pression of 'P in Xenopus laevis frogs increases the e$port of transcripts
that are other)ise inefficiently e$ported% (o)ever 'P needs adaptor proteins because it is
unable interact directly )ith mRN% lyGR/F protein interacts and bind to the mRN
recruiting 'P%
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mRNA localization[edit]
mRN locali-ation is critical for regulation of gene e$pression by allo)ing spatially regulated
protein production% 'hrough mRN locali-ation proteins are transcribed in their intended
target site of the cell% 'his is especially important during early development )hen rapid cell
cleavages give different cells various combinations of mRN )hich can then lead to
drastically different cell fates% RBPs are critical in the locali-ation of this mRN that insures
proteins are only transcribed in their intended regions% ?ne of these proteins is 7BP"% 7BP"
binds to beta+actin mRN at the site of transcription and moves )ith mRN into the
cytoplasm% >t then locali-es this mRN to the lamella region of several asymmetric cell types
)here it can then be translated%
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F&RP is another RBP involved in RN locali-ation% >t )as
sho)n that in addition to other functions for F&RP in RN metabolism, F&RP is involved in
the stimulus+induced locali-ation of several dendritic mRNs in neuronal dendrites%
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Translation[edit]
'ranslational regulation provides a rapid mechanism to control gene e$pression% Rather than
controlling gene e$pression at the transcriptional level, mRN is already transcribed but the
recruitment of ribosomes is controlled% 'his allo)s rapid generation of proteins )hen a signal
activates translation% 7BP" in addition to its role in the locali-ation of B+actin mRN is also
involved in the translational repression of beta+actin mRN by blocking translation initiation%
7BP" must be removed from the mRN to allo) the ribosome to properly bind and
translation to begin%
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RNA-binding activity and recognition of the RNA
sequence[edit]
RN+binding proteins e$hibit highly specific recognition of their RN targets by recogni-ing
their se*uences and structures%
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5pecific binding of the RN+binding proteins allo) them to
distinguish their targets and regulate a variety of cellular functions via control of the
generation, maturation, and lifespan of the RN transcript% 'his interaction begins during
transcription as some RBPs remain bound to RN until degradation )hereas others only
transiently bind to RN to regulate RN splicing, processing, transport, and locali-ation%
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>n
this section, three classes of the most )idely studied RN+binding domains (RN+
recognition motif, double+stranded RN+binding motif, -inc+finger motif) )ill be discussed%
RNA-recognition motif RR!"[edit]
'he RN recognition motif, )hich is the most common RN+binding motif, is a small protein
domain of :0+;0 amino acids that forms a four+stranded I+sheet against the t)o J+helices%
'his recognition motif e$erts its role in numerous cellular functions, especially in
mRNGrRN processing, splicing, translation regulation, RN e$port, and RN stability% 'en
structures of an RR& have been identified through N&R spectroscopy and H+ray
crystallography% 'hese structures illustrate the intricacy of protein+RN recognition of RR&
as it entails RN+RN and protein+protein interactions in addition to protein+RN
interactions% 2espite their comple$ity, all ten structures have some common features% ll
RR&s= main protein surfacesD four+stranded I+sheet )as found to interact )ith the RN,
)hich usually contacts t)o or three nucleotides in a specific manner% >n addition, strong RN
binding affinity and specificity to)ards variation are achieved through an interaction bet)een
the inter+domain linker and the RN and bet)een RR&s themselves% 'his plasticity of the
RR& e$plains )hy RR& is the most abundant domain and )hy it plays an important role in
various biological functions%
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#o$ble-stranded RNA-binding motif dsR%!"[edit]
'he dsRB&, :1+:0 amino+acid domain, plays a critical role in RN
processing, RN locali-ation, RN interference, RN editing, and translational repression%
lthough only three structures of dsRB&s have been currently discovered, all three
structures possess uniting features that e$plain ho) dsRB&s only bind to dsRN instead of
ds2N% 'he dsRB&s )ere found to interact along the RN duple$ via both J+helices and
I"+I3 loop% &oreover, all three dsRB& structures make contact )ith the sugar+phosphate
backbone of the ma.or groove and of one minor groove, )hich is mediated by the I"+I3 loop
along )ith the N+terminus region of the alpha heli$ 3% 'his interaction is a uni*ue adaptation
for the shape of an RN double heli$ as it involves 3D+hydro$yls and phosphate o$ygen%
2espite the common structural features among dsRB&s, they e$hibit distinct chemical
frame)orks, )hich permits specificity for a variety for RN structures including stem+loops,
internal loops, bulges or helices containing mismatches%
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&inc fingers[edit]
K7inc fingerK , 9artoon representation of the -inc+finger motif of proteins% 'he -inc ion (green) is coordinated
by t)o histidine and t)o cysteine amino acid residues%
99((+type -inc+finger domains are the most common 2N+binding domain )ithin the
eukaryotic genome% >n order to attain high se*uence+specific recognition of 2N, several
-inc fingers are utili-ed in a modular fashion% 7inc fingers e$hibit IIJ protein fold in )hich a
I+hairpin and a J+heli$ are .oined together via a 7nL3 ion% Furthermore, the interaction
bet)een protein side+chains of the J+heli$ )ith the 2N bases in the ma.or groove allo)s for
the 2N+se*uence+specific recognition% 2espite its )ide recognition of 2N, there has been
recent discoveries that -inc fingers also have the ability to recogni-e RN% >n addition to
99(( -inc fingers, 999( -inc fingers )ere recently discovered to employ se*uence+
specific recognition of single+stranded RN through an interaction bet)een
intermolecular hydrogen bonds and Watson+9rick edges of the RN bases% 99((+type -inc
fingers employ t)o methods of RN binding% First, the -inc fingers e$ert non+specific
interaction )ith the backbone of a double heli$ )hereas the second mode allo)s -inc fingers
to specifically recogni-e the individual bases that bulge out% 2iffering from the 99((+type,
the 999(+type -inc finger displays another mode of RN binding, in )hich single+stranded
RN is identified in a se*uence+specific manner% ?verall, -inc fingers can directly recogni-e
2N via binding to ds2N se*uence and RN via binding to ssRN se*uence%
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Role in embryonic development[edit]
9ra)ling C. elegans hermaphrodite )orm
RN+binding proteinsD transcriptional and post+transcriptional regulation of RN has a role in
regulating the patterns of gene e$pression during development%
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/$tensive research on the
nematode C. elegans has identified RN+binding proteins as essential factors
during germline and early embryonic development% 'heir specific function involves the
development ofsomatic tissues (neurons, hypodermis, muscles and e$cretory cells) as )ell
as providing timing cues for the developmental events% Nevertheless, it is e$ceptionally
challenging to discover the mechanism behind RBPs= function in development due to the
difficulty in identifying their RN targets% 'his is because most RBPs usually have multiple
RN targets%
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(o)ever, it is indisputable that RBPs e$ert a critical control in regulating
developmental path)ays in a concerted manner%
R%Ps in germline development[edit]
>n Drosophila melanogaster, /lav, 5$l and tra+3 are RN+binding protein encoding genes
that are critical in the early se$ determination and the maintenance of the somatic se$ual
state%
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'hese genes impose effects on the post+transcriptional level by regulating se$+
specific splicing in Drosophila% 5$" e$erts positive regulation of the femini-ing gene tra to
produce a functional tra mRN in females% >n C. elegans, RN+binding proteins including
F?M+", &?M+"G+6G+0 and RNP+6 regulate germline and somatic se$ determination%
Furthermore, several RBPs such as MN2+", MN2+4, 27+", PMN+" and ?&+"G+3 e$ert their
regulatory functions duringmeiotic prophase progression, gametogenesis, and oocyte
maturation%
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R%Ps in somatic development[edit]
>n addition to RBPs= functions in germline development, post+transcriptional control also
plays a significant role in somatic development% 2iffering from RBPs that are involved in
germline and early embryo development, RBPs functioning in somatic development regulate
tissue+specific alternative splicing of the mRN targets% For instance, &/9+; and BN9+:0
containing RR& domains locali-e to regions of hypodermis and nervous system,
respectively%
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Furthermore, another RR&+containing RBP, /H9+:, is revealed to locali-e in
embryonic e$cretory canal cells and throughout the nervous system during somatic
development%
R%Ps in ne$ronal development[edit]
7BP" )as sho)n to regulate dendritogenesis (dendrite formation) in hippocampal neurons%
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?ther RN+binding proteins involved in dendrite formation are Pumilioand Nanos,
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F&RP, 9P/B and 5taufen "
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Current research[edit]
K9>RBPK , 5tructure of the 9>RBP protein%
s RN+binding proteins e$ert significant control over numerous cellular functions, they have
been a popular area of investigation for many researchers% 2ue to its importance in the
biological field, numerous discoveries regarding RN+binding proteins= potentials have been
recently unveiled%
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RN+binding protein 5am8; controls the spatial and temporal compartmentali-ation of
RN metabolism to attain propersynaptic function in dendrites% Noss of 5am8; results in
abnormal posttranscriptional regulation and ultimately leads toneurological disorders such
as fragile H+associated tremorGata$ia syndrome% 5am8; )as found to interact )ith the mRN
encoding I+actin, )hich regulates the synaptic formation of the dendritic spines )ith
its cytoskeletal components% 'herefore, 5am8; plays a critical role in regulating synapse
number via control of postsynaptic I+actin mRN metabolism%
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KBeta+actinK , 5tructure of the 9'B protein%
Neuron+specific 9/NF family RN+binding protein BN9+:0 specifically binds to the
BBMBBMBMBBMB mRN stretch via its three RN recognition motifs for the e$on :a
selection in C. elegansD neuronal cells% s e$on :a is skipped due to its )eak splice sites in
non+neuronal cells, BN9+:0 )as found to specifically activate splicing bet)een e$on :a and
e$on ; only in the neuronal cells%
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'he cold inducible RN binding protein 9>RBP plays a role in controlling the cellular
response upon confronting a variety of cellular stresses, including short
)avelength ultraviolet light, hypo$ia, and hypothermia% 'his research yielded potential
implications for the association of disease states )ith inflammation%
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5erine+arginine family of RN+binding protein 5lr" )as found e$ert control on the polari-ed
gro)th in 9andida albicans% 5lr" mutations in mice results in decreased filamentation and
reduces damage to epithelial and endothelial cells that leads to e$tended survival rate
compared to the 5lr" )ild+type strains% 'herefore, this research reveals that 5R+like protein
5lr" plays a role in instigating the hyphal formation and virulence in C. albicans%
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