Table Of ContentAdvances in Experimental Medicine and Biology 925
Protein Reviews
M. Zouhair Atassi Editor
Protein
Reviews
Volume 17
Advances in Experimental Medicine
and Biology
Protein Reviews
Volume 925
Subseries Editor
M. Zouhair Atassi
More information about this series at http://www.springer.com/series/14330
M. Zouhair Atassi
Editor
Protein Reviews
Volume 17
Editor
M.ZouhairAtassi
BiochemandMolBiol
BaylorCollegeofMedicine
Houston,TX,USA
ISSN0065-2598 ISSN2214-8019 (electronic)
AdvancesinExperimentalMedicineandBiology
ISSN2520-1891 ISSN2520-1905 (electronic)
ProteinReviews
ISBN978-981-10-3709-2 ISBN978-981-10-3710-8 (eBook)
DOI10.1007/978-981-10-3710-8
LibraryofCongressControlNumber:2017938742
#SpringerNatureSingaporePteLtd.2017
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Preface
ProteinReviewsisabookserieswhichhasbeenpublishedbySpringersince
2005.Ithaspublished15printedvolumestodate(toseepreviousvolumes,
please go to http://www.springer.com/series/6876). Each volume was dedi-
catedtoaparticulartheme:
– ViralMembraneProteins:Structure,Function,andDrugDesign
– Thep53TumorSuppressorPathwayandCancer
– ProteomicsandProtein-ProteinInteractions
– ProteinMisfolding,AggregationandConformationalDiseases:PartA
– ProteinInteractions
– ProteinMisfolding,AggregationandConformationalDiseases:PartB
– CellStressProteins
– Actin-BindingProteinsandDisease
– DioxygenBindingandSensingProteins
– RibonucleaseP
– TheCircadianClock
– Post-TranslationalModificationsinHealthandDisease
– FoldingofDisulphideProteins
– TheNucleolus
– cp
Fromhereon,tospeedupthepublicationprocessandenhanceaccessibil-
ity,allarticleswillappearonlinebeforetheyarepublishedinaprintedbook.
The book series will appear as a subseries of Advances in Experimental
Medicine and Biology (http://www.springer.com/series/14330) in volumes,
eachofwhichwillfocusonagiventhemeorvolumesthatcontainreviewson
an assortment of topics, in order to stay up to date and to publish timely
reviewsinanefficientmanner.
TheaimofProteinReviewsistoserveasapublicationvehicleforreviews
that focus on crucial contemporary and vital aspects of protein structure,
function,evolutionandgenetics.Publicationswillbeselectedbasedontheir
importancetotheunderstandingofbiologicalsystems,theirrelevancetothe
unravelling of issues associated with health and disease or their impact on
scientific or technological advances and developments. Proteins linked to
diseasesortotheappearanceandprogressofdiseaseswillobviouslyprovide
v
vi Preface
essential topics that may be covered in this series. Moreover, proteins that
are, or can be, used as potential biomarkers or as candidates for treatment
and/or for the design of distinctive, new therapeutics will receive high
attentioninthisbookseries.
Theissuesmayincludebiochemistry,biophysics,immunology,structural
and molecular biology, genetics, molecular and cellular mechanisms of
action, clinical studies and new pioneering therapies. A given volume may
be focused on a particular theme or may contain a selected assortment of
differentcurrenttopics.
The authors of the articles are selected from leading basic or medical
scientists in academic or industrial organizations. The invited authors are
nominated by the editorial board or by experts in the scientific community.
However, interestedindividuals may suggesta topic for review and/ormay
proposeapersontoreviewacurrentimportanttopic.Colleaguesinterestedin
writingarevieworinguest-editingaspecialthematicissueareencouragedto
submittheirproposalsandthelistofauthorsofthesuggestedchapter/topics
totheeditorbeforesubmittingamanuscript.
The manuscripts are reviewed and evaluated in the usual manner by
experts in the field. The articles will be published online no later than
6weeksaftereditorialreviewandacceptance.
Itshouldbere-emphasizedthatProteinReviewswillpublishallaccepted
reviewarticlesonlinebeforetheyappearinprint.Andtherewillbenopage
orcolourchargesandnopageorcolourimagelimitations.
IhopethatProteinReviewswill continue toservethe scientific commu-
nityasavaluablevehicleforthedisseminationofvitalandessentialcontem-
porary discoveries on protein molecules and their immensely versatile
biologicalactivities.
M.ZouhairAtassi
Editor-in-Chief
Contents
AggregationofFETProteinsasaPathologicalChange
inAmyotrophicLateralSclerosis. . . . . . . . . . . . . . . . . . . . . . . . . 1
YoshiakiFurukawaandEiichiTokuda
StructuralChangesFundamentaltoGating
oftheCysticFibrosisTransmembraneConductance
RegulatorAnionChannelPore. . . . . . . . . . . . . . . . . . . . . . . . . . . 13
PaulLinsdell
DualRolesforEpithelialSplicingRegulatoryProteins1(ESRP1)
and2(ESRP2)inCancerProgression. . . . . . . . . . . . . . . . . . . . . . 33
AkiraHayakawa,MasaoSaitoh,andKeijiMiyazawa
ControllingAutolysisDuringFlagellaInsertion
inGram-NegativeBacteria. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
FrancescaA.HerliheyandAnthonyJ.Clarke
RegulationofSkeletalMuscleMyoblastDifferentiation
andProliferationbyPannexins. . . . . . . . . . . . . . . . . . . . . . . . . . . 57
Ste´phanieLangloisandKyleN.Cowan
HyaluronidaseandChondroitinase. . . . . . . . . . . . . . . . . . . . . . . . 75
WenshuangWang,JunhongWang,andFuchuanLi
FactorsthatControlMitoticSpindleDynamics. . . . . . . . . . . . . . 89
RobertaFraschini
SecretedPhospholipaseA2TypeIIA(sPLA2-IIA)
ActivatesIntegrinsinanAllostericManner. . . . . . . . . . . . . . . . . 103
YoshikazuTakadaandMasaakiFujita
TheSimpleandUniqueAllostericMachineryof
ThermuscaldophilusLactateDehydrogenase. . . . . . . . . . . . . . . . 117
HayaoTaguchi
ReductionofChemicallyStableMultibonds:
Nitrogenase-LikeBiosynthesisofTetrapyrroles. . . . . . . . . . . . . . 147
GunhildLayer,JoernKrausze,andJürgenMoser
Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
vii
AdvExpMedBiol-ProteinReviews(2017)1:1–12
DOI10.1007/5584_2016_32
#SpringerInternationalPublishingSwitzerland2016
Publishedonline:17June2016
Aggregation of FET Proteins
as a Pathological Change
in Amyotrophic Lateral Sclerosis
Yoshiaki Furukawa and Eiichi Tokuda
Abstract
Amyotrophiclateralsclerosis(ALS)isafatalmotorneurondiseasethatis
characterizedbytheformationofabnormalinclusionsinneurons.While
thepathomechanismofALSremainsobscure,anumberofproteinshave
been identified in the inclusion bodies, and the pathological roles of
RNA-binding proteins have been increasingly emphasized. Among
those, the FET proteins (FUS, EWSR1, TAF15) were recently identified
as RNA-binding proteins in pathological inclusions of ALS and other
neurodegenerative diseases; moreover, mutations in the genes encoding
theFETproteinswerefoundtobeassociatedwithfamilialformsofALS.
FETproteinsarenormallylocalizedinthenucleus,buttheintroductionof
pathogenicmutationsinFETproteinsleads totheir abnormalredistribu-
tiontothecytoplasm,wheretheyformaggregates.Whilefurtherinvesti-
gation will be requiredto understand the intracellular factors controlling
theaggregationpropensitiesofFETproteins,theyarethoughttolosetheir
physiologicalfunctionsandbecometoxicthroughtheirmisfolding/aggre-
gation.Here,wewillbrieflyreviewrecentadvancesofourunderstanding
of the physiological functions and aggregation behavior of FET proteins
invivoaswellasinvitro.
Keywords
FUS (cid:129) FET family proteins (cid:129) Amyotrophic lateral sclerosis (cid:129) Protein
aggregation(cid:129)Neurodegenerativediseases
1 Introduction
Y.Furukawa(*)andE.Tokuda Amyotrophic lateral sclerosis (ALS) is a late-
LaboratoryforMechanisticChemistryofBiomolecules,
onset progressive disease with degeneration of
DepartmentofChemistry,KeioUniversity,3-14-1
motor neurons. Most of the cases (>90 %) are
Hiyoshi,Kohoku,Yokohama223-8522,Japan
e-mail:[email protected] sporadic, and the pathomechanism remains
1
2 Y.FurukawaandE.Tokuda
obscure.Nocuresarecurrentlyavailableforthis (FTLD-U),neuronalintermediatefilamentinclu-
devastating disease, but increasing numbers of sion disease (NIFID), and basophilic inclusions
genes responsible for familial forms of ALS body disease (BIBD), which are collectively
(fALS) have been recently identified (http:// calledFTLD-FUS(Mackenzie et al.2010b).No
alsod.iop.kcl.ac.uk). Mutations in SOD1 gene genetic abnormalities of FUS have been
were first identified as a cause of fALS in 1993 identifiedinFTLD-FUS,anditremainsunknown
(Rosen et al. 1993), and transgenic rodents howFUSfacilitatesthesepathologicalchanges.
expressing SOD1 with pathogenic mutations As described below, both TDP-43 and FUS
have long served as a standard model in the have a “prion-like” domain with low amino
research of ALS (Turner and Talbot 2008). In acid complexity (Gitler and Shorter 2011;
2006, Arai et al. (2006) and Neumann Polymenidou and Cleveland 2011). Prion
et al. (2006) reported milestone papers where a proteins in mammals (PrP) and yeast (e.g.
DNA/RNA-binding protein, TDP-43, was Sup35) are equipped with a low complexity
identified as a constituent of pathological region, which is essential for the formation of
inclusions in sporadic ALS patients. Soon after fibrillar aggregates and also for the infectivity
the identification, several ALS-causing and transmissibility as prions (Chien
mutations were successively reported in the et al. 2004). The high aggregation propensities
TARDBP gene, which encodes for the TDP-43 oftheprion-likedomainsinTDP-43andFUSare
protein (Gitcho et al. 2008; Kabashi et al. 2008; consistentwiththeirinvolvementinpathological
Sreedharanetal.2008;VanDeerlinetal.2008). inclusions observed in motorneurons of ALS
While mutations in TARDBP have been patients, which has spurred many researchers to
described in ~4 % of familial and ~1.5 % of investigate the aggregation mechanism of
sporadicALScases,theneuropathologyinmost TDP-43/FUS. Very interestingly, the other pro-
cases of sporadic ALS is characterized by the tein candidates to cause ALS were surveyed by
abnormal cytoplasmic accumulation of TDP-43 systematic screening of RNA-binding proteins
in neurons and glia (Mackenzie et al. 2010a). using yeast, among which missense mutations
Importantly, TDP-43-positive cytoplasmic in TAF15, EWSR1 and hnRNPA1 were indeed
inclusions have been characterized in almost identified in ALS patients (Couthouis
half of the frontotemporal lobar degeneration et al. 2011, 2012; Kim et al. 2013). All of these
(FTLD) cases (Mackenzie et al. 2010a). Thus, proteinshaveaprion-likedomainwithlowcom-
TDP-43 has become the most important player plexityandhaveadomainorganizationwhichis
asapathologicalproteininALS. very similar to that of TDP-43 (hnRNPA1) or
In 2009, mutations in a gene encoding for FUS(TAF15,EWSR1).So,theremaybeacom-
FusedinSarcoma(FUS)werefoundtobecausa- monpathwayforthoseRNA-bindingproteinsto
tive in a subset of ALS cases (ALS-FUS) gain some toxicity that leads to ALS. In this
(Kwiatkowski et al. 2009; Vance et al. 2009). review, we will focus upon the FET proteins
Given that FUS is also a DNA/RNA-binding (FUS,EWSR1,andTAF15)andbrieflysumma-
protein, many researchers have now focused rizerecentadvanceofourunderstandingoftheir
upon the possible involvement of DNA/RNA pathologicalrolesinALS.
metabolism in the pathomechanism of ALS.
ALS-FUS accounts for ~4 % of familial and
<1 % of sporadic ALS cases, and its neuropa- 2 Structure and Physiological
thology has been characterized by abnormal Functions of FET Proteins
FUS-positive inclusions in the cytoplasm of
neurons and glia (Mackenzie et al. 2010a). FUS FUS, EWSR1, and TAF15 constitute the FET
has also been identified as a component of the protein family and are normally localized in the
inclusions in atypical frontotemporal lobar nucleus (Tan and Manley 2009). While it
degeneration with ubiquitin-positive inclusions remains obscure if there is specificity or
