supplementary information · supplementary information preso1 dynamically regulates group i...

Supplementary Information

Preso1 dynamically regulates group I metabotropic glutamate receptors.

Jia–Hua Hu, Linlin Yang, Paul J. Kammermeier, Chester G. Moore, Paul R. Brakeman, Jiancheng Tu, Shouyang Yu, Ronald S. Petralia, Zhe Li, Ping–Wu Zhang, Joo Min Park, Xinzhong Dong, Bo Xiao, Paul F. Worley

Contents

Supplementary Figures 1–13

Nature Neuroscience: doi:10.1038/nn.3103

1 100

Human (1) --------------------------------------------------

Rat (1) --------------------------------------------------

Mouse (1) --------------------------------------------------

Chicken (1) --------------------------------------------------

Zebrafish (1) --------------------------------------------------

Drosophila (1) MLLPSGRSNSDVYPLQNVNTTTASASSVGGSKPLLLTRTSSPQLTTLQTL

--------------------------------------------------

--------------------------------------------------

----------------------------------------------------------------------------------------------------

--------------------------------------------------

NGGGIGGGGGANAHTALRTNSSAAFAATLAQETAGSLPGTGTQATATTST

101 200

Human (1) --------------------------------------------------Rat (1) --------------------------------------------------

Mouse (1) --------------------------------------------------

Chicken (1) --------------------------------------------------

Zebrafish (1) ---------------------------------------------MITVC

Drosophila (101) TASATTTTTAISTTTTAISTTATATATTAAASVNAVNTDFGAGALYGPIL

-------------------- S

---------------------------------------MRSHSCHRTKS

---------------------------------------MRSHSCHRTKS

---------MEEAEMNPSEKLATSFKVIWFTCVGKG MR RTDHRNKS

NWVINSSSSFFTRSSFPPQPFVPQCHCSPPPKLQIGRTFER RDKS

GPSHAGNAPIGNWGEIDRHLDAVQEKLKAGWTVHLAKDGRLYYCNHLTQS

201 300

Human (20) SG-----------------WPPPSGTWGLSQVPPYGWEM TANRDGRDYFI

Rat (12) SG-----------------WPPPSGTWGLNQVPPYGWEMMTNRDGRDYFI

Mouse (12) SG-----------------WPPPSGTWGLNQVPPYGWEMMTNRDGRDYFI

Chicken (42) SG-----------------WPHPSGTWSLNQGTPYGWEMTANRDGRDYFI

Zebrafish (56) FPRLYIVFTSTVLCLNGE CQTCVSNVAVMKEESKSCVICPHGKKKYRSIL

Drosophila (201) SG-----------------WLPACEDWSKHEELSYGWE RAIDSKGRSYYI

NHMTQAIPFDDPRLESCQIIPPAPRKVEMRRDPVLGFGFVAGSEKPVVVR

NHMTQAIPFDDPRFDSCQIIPPAPRKVEMRRDPVLGFGFVAGSEKPVVVR

NHMTQAIPFDDPRFDSCQIIPPAPRKVEMRRDPVLGFGFVAGSEKPVVVRNHMTQSATFEDPRIESCQITPPAPRKVEMRRDPVLGFGFVAGSEKPVVVR

HHLSQSSSLEEVRVDVEKFVPPAPRKVEMRRDPVLGFGFVAGSE KPVVVR

NHLNKTTTYEAPECIRWDEHPPEPRLVQLQRSASLGFGFVAGSERPVIVR

301 400

Human (103) SVTPGGPSEGKLIPGDQIVMINDEPVSAAPRERVIDLVRSCKESILLTVI

Rat (95) SVTPGGPSEGKLIPGDQIVMINDEPVSAAPRERVIDLVRSCKESILFTVI

Mouse (95) SVTPGGPSEGKLIPGDQIVMINDEAVSAAPRERVIDLVRSCKESILLTVI

Chicken (125) SVTPGGPSEGKLIPGDQIIMINDEPVSTAPRERVIDLVRSCKESILLTVV

Zebrafish (156) SVTPGGPSEGKLIPGDEIVMINEEPVSSAPRERVIDLVRSCKESIILTVV

Drosophila (284) FVTEGGPSIGKLQPGDQILAVNGEDVKDAPRDHVIQLVRACETQVSLLVC

QPYPSPKS-----AFISAAKKARLKSNPVKVRFSEEVIIN-----GQVSE




QPYPSPKS-----AFISAAKKAKLKSNPVKVRFAEEVIIN-----GQVPE

QPMAHCVLPGRKSTLLSAGKRAKLRTRPSRVRFAESVCVNGAPLFPPSAF

401 500

Human (193) TVKDNSLLFMPNVLKVYLENGQTKSFRFDCSTSIKDVILTLQEKLSIKGI

Rat (185) TVKDNSLLFMPNVLKVYLENGQTKSFRFDCSTSIKDVILTLQEKLSIKGI

Mouse (185) TVKDNSLLFMPNVLKVYLENGQTKSFRFDCSTSIKDVILTLQEKLSIKGI

Chicken (215) TVKDNSLLFMPNVLKVYLENGQTKSFRFDCSTSIKDVILTLQEKLSIKCI

Zebrafish (246) SVKDNFLLFMPNVLKVFLENGQTKSFKFDCNTSIK---------------

Drosophila (384) SLGDICVPPMANVLKVFLENGQTKSFKYDATTTVQDVVSSLLDKLCLCCG

EHFSLMLEQRTEGAGTKLLLLHEQETLTQVTQRPSSHKMRCLFRISFVPK

EHFSLMLEQRTEGAGTKLLLLHEQETLTQVTQRPSSHKMRCLFRISFVPK

EHFSLMLEQRIEGAGTKLLLLHEQETLTQVTQRPSSHKMRCLFRISFVPK

EHFSLMLEQRVEGSGTKLLLLHEQETLTQVTQRPSSHKMRCLFRISFVPK

--------------------------------------------------

ELFSLVLEHVKSLKRNKLTLLDPQESLARIAARPGAHKLRCLFRITFVPI

501 600

Human (293) DPIDLLRRDPVAFEYLYVQSCNDVVQERFGPELKYDIALRLAALQMYIAT

Rat (285) DPIDLLRRDPVAFEYLYVQSCNDVVQERFGPELKYDIALRLAALQMYIAT

Mouse (285) DPIDLLRRDPVAFEYLYVQSCNDVVQERFGPELKYDIALRLAALQMYIAT

Chicken (315) DPIDLLRRDPVAFEYLYVQSCNDVVQERFGPELKYDIALRLAALQMYIAT

Zebrafish (281) --------------------------------------------------

Drosophila (484) SAAELAQRDLNALDYLYMQCCNDVNQERFAPELQPELALRLAALHMHQHA

VTT-KQTQKISLKYIEKEWGLETFLPSAVLQSMKEKNIKKALSHLVKANQ




-----------------EWGLAQFLPPAVLSSMKEKNIKKALTHILKTNQ

LANNFAPAKLTVKLVEREFGLERFVPVSLFEGMKRKELRRLISHFLKVNA

601 700

Human (392) NLVPPGKKLSALQAKVHYLKFLSDLRLYGGRVFKATLVQAEKRSEVTLLV

Rat (384) NLVPPGKKLSALQAKVHYLKFLSDLRLYGGRVFKATLVQAEKRSEVTLLV

Mouse (384) NLVPPGKKLSALQAKVHYLKFLSDLRLYGGRVFKATLVQAEKRSEVTLLVChicken (414) NLVPPGKKLSALQAKVHYLKFLSDLRLYGGRVFKATLVQGEKRSEVTLLV

Zebrafish (314) NLVPPGKKLTALQAKVHYLKYLSDLRLYGGRVFKSTLVQGEKHTEVTLLVDrosophila (584) EMTGSSKVLTQLQAKLHYLDIIASLPSYGAKCFSTNQREG---MERVLLV

GPRYGISHVINTKTNLVALLADFSHVNRIEMFSEEESLVRVELHVLDVKP

GPRYGISHVINTKTNLVALLADFSHVNRIEMFTEEESLVRVELHVLDVKP

GPRYGISHVINTKTNLVALLADFSHVNRIEMFTEEESLVRVELHVLDVKP

GPRYGISHVINTKTNLVALLADFSHVNRIEMFTEDESSVRVELHVLDVKP

GPRYGISHVINTKTNLVALLADFSHVNRIEMYTEDERNVRVELHVLDVKP

SPRFGLS QISSARNSVPQPISAIEDFTHVVVHREDDITCSVSIYMLGDRA

D-domain

Figure S1

R

R

KLSSHRTK

DGSR

IA-----------MDVFSFVK

AIA


701 800

Human (492) ITLLMESSDAMNLACLTAGYYRLLVDSRRSIFNMANKKNTATQETGPENK

Rat (484) ITLLMESSDAMNLACLTAGYYRLLVDSRRSIFNMANKKNAGTQDTG TENK

Mouse (484) ITLLMESSDAMNLACLTAGYYRLLVDSRRSIFNMANKKNAGTQDTG SENK

Chicken (514) ITLLMESSDAMNLACLTAGYYRLLVDSRRSIFNMANKKNAGNRETGIENR

Zebrafish (414) ITLIMESSDAMNLACLTAGYYRLLVDSRRSIFNMANN----SNTAGHDTR

Drosophila (681) VKFIMEDRDACEFSLVLGGYYRLLTG---NVLNVLRERE PNEEDNAPAFL

GKHNLLGPDWNCIPQMTTFIGEGEQEAQITYIDSKQKTVEITDSTMCPKE

GKHNLLGPDWNCMPQMTTFIGEGEQEAQITYIDSKQKAVEMTDSTLCPKE

GKHNLLGPDWNCMPQMTTFIGEGEQEAQITYIDSKQKTVEMTDSTLCPKE

GKHNLLASE WNCVPKTTTFLADGDQETQMPFGDPKQKAIDVSESLLCQKE

IKHNYQAID WNYG--T----CGGCNEPHPEYAVCGRRECDISPSEIHQAH

SQHTVLPAS WSYLLPFHNRAHSVNFLITPPYHPMPQQAVLSQPQPVQQQQ

801 900

Human (592) HRHLYIDNAYSSDGLNQQLSQPGEAPCEADYRSLAQRSLLTLSGPETLKK

Rat (584) HRHLYIDNTYSSDELSQPLTQPGDAPCEADYRSLAQRSLLTLSGPDTLKK

Mouse (584) HRHLYIDNSYSSDELNQPLTQPGDAPCEADYRSLAQRSLLTLSGPDTLKK

Chicken (614) HRHLYIENTYNSGGFDQHLTKQDPTDAEES-RNFNQHSLLSLSGLESSKK

Zebrafish (504) HMHGDEKAERQSRGSHMHAQPYFNIPKGKP--------------------

Drosophila (778) QLSYATDLDLHSVMATELLEEAAKDSGLSDSSGSNYCSESRTQLAVEA KN

AQESPRGAKVSFIFGDFALDDGISPPTLGYETLLDEGPEMLEKQRNLYIG

AQESPRGAKVSFIFGDLALDDGMSPPTLGYERMLDENPEMLEKQRNLYIS

AQESPRGAKVSFIFGDLALDDGMSPPTIGYERMLEENPEMLEKQRNLYIS

AQDSPRGAKVSFIFGDHNLDG-INPQTLGYERLLDESPEVLEKQRAIYIN

Q-ESPRSAKVSFIFGDPPLDS-VNPQNLGYHRLMEDIPEVLEEHR-YLYA

EQVLRRVQELQKLVQCSEQYLSEQEQELQHVPLQQLQQQQREQTQQQMGQ

901 1000

Human (692) SANDMKGLDLTPEAEGIQFVENSVYANIG--DVKSFQAAEGIEEPLLHDI

Rat (684) SANDMKNLDLTPDTDSIQFVANSVYANIG--DVKNFEAPEGIEEPLLHDI

Mouse (684) SANDMKNLDLTPDTDSIQFVANSVYANIG--DVKNFEAPEGIEEPLLHDI

Chicken (712) NANDIKGLELSPDAESIQFATNAVYATIN--DGKIFGAAEGIEEPLLHDI

Zebrafish (581) QQKDYKPLEASLEVDGFQYGTHMVYG-----DAKIFGTTEGIEEPLLHDI

Drosophila (878) SVAMLEFDSDCDSLNSSKVSSTEESNHVSQPSLKHSDSLTLLAETISHEL

CYAENTDDAEDEDEVSCEEDLVVGEMNQP----------AILNLSGSSDD

CYAENTDDAEDEDEVSCEEDLVVSEINQP----------AILDLSGSSDD

CYAENTDDAEDEDEVSCEEDLVVGEMNQP----------AILDLSGSSDD

CYAENTDDAEDEDEVSCEEDIMVGEINRP----------ALLSLSGSSDD

CYAETTDDAEEDDDISCEEDMMM MMGEMK------DKANSLLSLSESSDD

TGITQGLNAIPEPISASAPPTPA TPKRKPSLCSTS-SPRPQRKLNGFSQL

1001 1100

Human (792) IIDLTSLPPPE--GDDNEDDFLLRSLNMAIAAPPPGFRDSSDEEDSQSQA

Rat (772) IIDLTTLPPPE--GDDNEDDFLLRSLNMAIAAPPPGFRDSSDEEDTQSQA

Mouse (772) IIDLTTLPPPE--GDDNEDDFLLRSLNMAIAAPPPGFRDSSDEEDTQSQA

Chicken (800) IIDLTSLPPPE--GDDNEDDFLLHTLNMAIAAPPPGFRDSSDEEDSQNQA

Zebrafish (670) IIDLTSLPPPPEGDYEEDSDDLLESLNLAIAAPPPGFRDSSDEDDHHDRK

Drosophila (977) LSDLQALGTDFSQSESDSESVASPAQSPTTRRPQQLLQAGSKQQQQQQQH

ASFPEDK---EKGSSLQNDEIPVSLIDAVPTSAEGKCEKGLDNAVVSTLG

TSFHENK---EQGSSLQNEEIPVSLIDAVPTSAEGKCEKGLDPTVVSTLE

TSFHEDK---EQGSSLQNEEIPVSLIDAVPTSAEGKCEKGLDPAVVSTLE

TQPRDDK---EQASNLGSDDIPVSLIDAVPTNTEGKCEKGLDDAVVSTLQ

MSKN---------------DIPVSLIDSVPTQVAGGSEEVFN DAVVSTLQ

QQLAQRSSFGLHSPDGTHFGAETKDYNLREYLQQLKEISNVP DTDVAARQ

1101 1200

Human (875) ALEALSVSEEQQTS DNSG---VAILRAYSPESSSDSGNETNSSEMTESSE

Rat (867) ALEALSE--EQQKSENSG---VAILRAYSPESSSDSGNETNSSEMTEGSE

Mouse (867) ALEALSE--EQQKSENSG---VAILRAYSPESSSDSGNETNSSEMTEGSE

Chicken (895) ALEALAASEEQQTNDNSG---VAILRAYSPESSSDSGNETNSSEMTESSE

Zebrafish (755) ALEALAASEDQSHPQSDNSSGVEISRSFSPESSSDSGNETNSSEMTESSE

Drosophila (1077) LSEIYGFEVREDTFIETDTDLIDLRAIPPPQTPDELDSLSLLNAAPPKGF

LATAQKQSENLSRMFLATHEGYHPLAEEQTEFPASKTPAGGLPPKSSHAL

LAAAQKQSESLSRMFLATHEGYHPLAEEQTEFPTSKTPSVGLPPKSSHGL

LAAAQKQSESLSRMFLATHEGYHPLAEEQTEFPTSKAPSVGLPPKSSHGL

LAAAQKHSENTARMFLTTSEGYQPLVEEQTEFPIAKSQAGGPGMKSSQPL

LAAAQKLSENSLKMFVATAEGYQTLAEEETEFRLAPSLDDPQSS------

EGKAEELDSFLQQMLVAPPTQKATPAKELTPEEIMSFIIPPPPNLEAQPE

1201 1300

Human (972) AAR---PATDLPPKVVPSKQLLHSDHMEMEPETMETKSVTDYFSKLHMGS

Rat (962) AAR---PATDLPPKVVPSKQILHSDHMEMEPETMETKSVTDYFSKLHMGS

Mouse (962) AAR---PATDLPPKVVPSKQILHSDHMEMEPETMETKSVTDYFSKLHMGS

Chicken (992) AGC---QAADLQSKVVPSKQILHSDNMEMEPETMETKSVTDYFSKLHMGS

Zebrafish (849) -----------------AVANLRSDHFEMEPETMETKSLTEYFSKMHRDV

Drosophila (1177) RPEECLYSNSVQAKREFFQAVANGNNSIQQNNHKDQAAHVIEYPTVERKS

VAYSCTSKRKSKLADGEGKAPPNGNTTGKKQQGTKTAEMEEEASGKFGTV

VAYSCTSKRKSKLAEGEGKCPLSGNVPGKKQQGTKIAETEEDTKGKVGTV

VAYSCTSKRKSKLPEGEGKSPLSGNIPGKKQQGTKIAEIEEDTKGKAGTVLVYSCTSKRKSKMTESEVKAPSDGNATVKKQQGTKKAETDEELKAKFGTI

MRGMAQGKVEEQDS GMKSSAEAAARQLN--------IAESEDLVGMYSNF

KFSCCPTSKKEEAA SLEEAAPLQPPPRTPAIEQTTPPPARPPKSAELLQR

1301 1400

Human (1069) SSRDSQHLSTFNLERTAFRKDSQRWYVATEGGMAEKSGLEAATGKTFPRA

Rat (1059) SSRDNPHLSTFNLERTAFRKDSQRWYVASDGGVVEKSGVEAPAMKAFPRG

Mouse (1059) SSRDNPHLSTFNLERTAFRKDSQRWYVASDGGVVEKSGMEAPAMKVFPRG

Chicken (1089) SARDSQRLSTFNVERTAFR---QRWYGADDGAADKPS-PETANGKTFPRV

Zebrafish (924) NGRDSQCSAPFDMESMSYAFQ---------------------GSNQRLHM

Drosophila (1277) YSPKKQVRIVGHQPVVSVPLRELCPPQLPPRSSPTASSEPATPQTATPAT

SGLGAREAEGKEEGAPDGETSDGSGLGQGDRFLTDVTCASSAKDLDNPED

PGLGNREAEGKEDGTMEGEADDASGLGQGERFLSDMACVASAKDLDNPED

PGLGNREAEGKEDGTVEGGADDASVLGQGDRFLTDMACVASAKDLDNPED

PVRGKTETDCKDEVDPEVDQDDTSGLSQGENFLSDMTPVSSAKDLNDAED

ILNNKSEEHIYSEVAGDSAPLHADRVAQKVSLEDSIDLNASSPAKEQYLV

SAVSAPKKPPLPPIANRPRPVNGTPTPVSNTSPPIPATTRLPNAHSNGGQ

1401 1500

Human (1169) ADSSTCDHPSKLPEADESVARLCDYHLAKRMSSLQSEGHFSLQSSQGSSV

Rat (1159) TDSPTCDHATKLPEAEDNVARLCDYHLAKRMSSLQSEGHFSLQSSQGSSV

Mouse (1159) TDSPSCDHATKLSEAEDNVARLCDYHLAKRMSSLQSEGHFSLQSSQGSSV

Chicken (1185) TDLSADDHPSKLPEAEQSVARLCEYHLAKRMSSLQSEGHFSLQSSQCSSV

Zebrafish (1003) ERARSEHQQSKGASSEQEVTRLYEYHLSKRMSSLQSE GVHSLQSSQCSSI

Drosophila (1377) PTLPKKPQQLHGEKLFIKNGHLIDGEALLAKTDVAMA GLLIKLDQVAAQC

DAGCGTGSSGSACATPVESPLCPSLGKHLIPDASGKGVNYIPSEERAPGL

DTGCGPGSSSSACATPVESPLCPSMGKHLIPDASGKGGSYISPEERVAGH

DTGCGPGSSSSACATPVESPLCPSMGKHMIPDASGKGGRYISPEERAPGH

DAGCSTG--SSTCATPVESPLCTSDIKHVISDPSMKGIAYIPADERAAIL

DAGCSTG--SSSCVTPMDSPLCTVDSVHLHTESSMKGLGYTNQNVDGTFL

SAAQSAGGGTSIDEDKFQRARNELTEQTLALVTASKFLVASMSDMTLINL

Homer site


1501 1550Human (1269) PNHGATFKELHPQTE-----------------------------------

Rat (1259) PNHGATFKELHPQTE-----------------------------------

Mouse (1259) PNHGATFEELHPQTE-----------------------------------

Chicken (1283) SNHGTTYKDLHQQPE-----------------------------------

Zebrafish (1101) RKHHGQAGAESGREGSQRLPKIRETTVVFFIATVYMLSSPCLVDICSDAA

Drosophila (1477) PDHLTSCLTAIRRITELAQDMTR---------------------------

-----------------------------GMCPRMTVPALHTAINTEPLF

-----------------------------GMCPRMTVPALHTAINADPLF

-----------------------------GMCPRMTVPALHTAINADPLF

-----------------------------AVCHRMTVPVTHSAINAEPLF

DGDKRGFALTECPSSSSSRAQLVLCQARGDGTSRMLPCLLVHSASVHPLW

-------------------------HTSAP LQTRNIVLKVHDVASSFREL

1601 1637

Human (1305) GTLRDGCHRLPKIKETTV-------------------

Rat (1295) GTLRDGCHRLPKIKETTV-------------------

Mouse (1295) GTLRDGCHRLPKIKETTV-------------------

Chicken (1319) GTLREGCHRIPKIKETTV-------------------

Zebrafish (1201) LPQGGGKGILNKTTMGSGSIHTFYGNEMAVIIQAVVR

Drosophila (1525) VGVQIGPIGAGQLALQAECLANVLATLLRSLRVFSP-

Supplementary Figure 1: The amino acid sequence alignment of Preso1 from various creatures. Red residues shaded in yellow are identical in all the predicted proteins, dark blue residues shaded in light blue are identical in > 50% of the predicted proteins, similar residues are shown in black shaded in green. D–domain and Homer binding site are indicated.


101 200

hPreso1 (101) PGGPSEGKLIPGDQIVMINDEPVSAAPRERVIDLVRSCKESILLTVIQPY

hPreso2 (77) PGGPSENKLLAGDQIVAINEEDVSEAPRERLIELIRSAKEFIVLTVLHTH

PSP-KSAFISAAKKARLKSNPVKVRFSEEVIINGQVSETVKDNSL

FMPN

hPreso3 (81) AGGSAHGKLFPGDQILQMNNEPAEDLSWERAVDILREAEDSLSITVVRCTSGVPKSSFLTEEKRARLKTNPVKVHFAEEVLISGHS----QGNS

CMPN

QSP-KSAFISAAKKAKLRSNPVKVRFSEQVAVGETDAKMMKKEA

LIPN

201 300

hPreso1 (200) VLKVYLENGQTKSFRFDCSTSIKDVILTLQEKLSIKGIEHFSLMLEQRTE

hPreso2 (176) VLKVFLENGQIKSFTFDGRTTVKDVMLTLQDRLSLRFIEHFALVLEYAGP

GAGTKLLLLHEQETLTQVTQRPSSHKMRCLFRISFVPKDPIDLL

DPVA

hPreso3 (177) VLKLYLENGQTKAFKFEANTTVKDIILTVKEKLSIRSIEYFALALEEQYSIS--RLHLLHEEELIQQVVEREESHDYRCLFRVCFVPKDPLDLLK

EDPVA

EQNHKFLLLQDKQPLAYVVQRTHYHGMKCLFRISFFPKDPVELL

DPAA

301 400

hPreso1 (300) FEYLYVQSCNDVVQERFGPELKYDIALRLAALQMYIATVTTKQTQKISLK

hPreso2 (276) FEYLYIQSRNDVIRERFGMDPKPEMLLGLAALHIYITVSATRPSQKISLK

YIEKEWGLETFLPSAVLQSMKEKNIKKALSHLVKANQNLVPPGKK

--LSA

hPreso3 (275) FEYLYLQSCSDVLQERFAVEMKCSSALRLAALHIQERIYACAQPQKISLKYIEKDWGIENFISPTLLRNMKGKDIKKAISFHMKRNQNLLEPRQK

QLISA

NVEKEWGLEPFLPPSLLQVIKEKNLRKSLSQQLKAHQTHPSCGTK

--GSA

401 500

hPreso1 (400) LQAKVHYLKFLSDLRLYGGRVFKATLVQAEKRSEVTLLVGPRYGISHVIN

hPreso2 (376) IQAKLQYLRILNELPTFTGVLFNTVGLD- KQSATTLLVGPRHGISHVID

TKTNLVALLADFSHVNRIEMFSEEESLVRVELHVLDVKPITLLME

SSDAM

hPreso3 (375) AQLRLNYLQILGELKTYGGRIFNATLMLQDRESYIALLVGAKYGISQVINSKLNIMSTLAEFANISRVELTEESEKVSVVKVYLQDVKVLTLLLE

SNSAK

LKTNLTTVLSEFSKISKIQLFRENQGVARVETSIMDAKPLVLLME

WPEAT

501 600

hPreso1 (498) NLACLTAGYYRLLVDSRRSIFNMANKKNTATQETGPENKGKHNLLGPDWN

hPreso2 (473) NFACLIAGYCRLLLDSRKMVFSRPASQPLPPPMIKADYMHSAHRPVTGGH

CIPQMTTFIGEGEQEAQITYIDSKQKTVEITDSTMCPKEHRHLYI

DNAYS

hPreso3 (475) DLACLIAGYYRLLVDPVTSIFLWPGNKQQAHRVSAEEGYESRACSDSEESSEVDCVLEPLSDRRLVKLAPCRSLIK-------------------

EEQPP

LGKKESSYVG-----------------------------------

S

601 700

hPreso1 (598) SDGLNQQLSQPGEAPCEADYRSLAQRSLLTLSGPETLKKAQESPRGAKVS

hPreso2 (538) VGTSPRKSSRCTPPPADSELVSFCYLHMREQ------RKEQESRTDVNEN

1 100

hPreso1 (1) FVKIAK HRTKSSGWPPPSGTWGLSQVPPYGWEMTANRDGRDYFINHM

hPreso2 (1) ---MET QRVQDRLLAAPGCSSPSGQQELFSSHVMQEES---------

TQAIPFDDPRLESCQIIPPAPRKVEMRRDPVLGFGFVAGSEKPVV

VRSVT

hPreso3 (1) MEELETSLFQTRKAHRIEQMVARWLRRSRDSSARAKVAAADG---------------PARNPTQTLIPVRHTVKIDKDTLLQDYGFHISESLPLT

VVAVT

-------ANDMECEQLPAEILRQVTVHRDPIYGFGFVAGSERPVV

VRSVR

FIFGDFALDDGISPPTLGYETLLDEGPEMLEKQRNLYIGSANDMK

LT

hPreso3 (556) GNSPTPEVARRGPSTCGASSTTDSAESEASDSANTESRGYRTSGSSESMDALEEDDLDTCSSSRSTFFHFGSPGLAESIDSDSQEERSGIETSGF

LD

LIFFEETRPRTKSDPTS----------------------------

701 800

hPreso1 (698) PEAEGIQFVENSVYANIGDVKSFQAAEGIEEPLLHDICYAENTDDAEDED

hPreso2 (600) -KSSGQGYEVVPDDFDAASLDHEPCASRARSYTLDNSLGAEALNFYCDSC

EVSCEEDLVVGEMNQPAILN------------LSGSSDDIIDLTS

LPPP-

hPreso3 (656) LAQRANPQCQKTEFSESAALETFGWAPELSTVRLDPRLYEGSHADYYSLCSSVSPASYLSDSSESTASRQGGAPPAWGQQGWTEAQPSSMLEPLA

LHPPL

KAKLQEQLGPRKGGKPGSS-----------------RDNIVDLMS

LPPPG

801 900 hPreso1 (786) EGDDNEDDFLLRSLNMAIAAP--PPGFRDSSDEEDS-QSQAASFPEDKEK

hPreso2 (677) SEEEEEEEDETTSLLPAIAAP--PPGFRDNSSDEDDPKRRAVQSQEQGRH

G------SSLQNDEIPVSLIDAVPTSAEGKCEKGLDNAVVSTLGA

ALS

hPreso3 (756) AFEDGSSDEEYYDAADKLTPPGPPSGPRDVSTAEPSATSLQNKASTSSPENSLPCGPDGRQPSRRGGVKKYAKTLRKRRSFLQTDDTSQVSFPLV

PSASL

L------RGLLYDEIPVTLIDSVQTRTVRDHAQELDDALVSTLQA

ALA

901 1000

hPreso1 (876) VSEE---QQTSDNSGVAILRAYSPESSSDSGNETNSSEMTESSELATAQK

hPreso2 (768) ASEDGPHPPPPQTAGLIVLATITPESSLDSGHETNSSELTDMSEMMSAMK

QSENLSRMFLATHEGYHPLAEEQTEFPASKTPAGGLPPKSSHALA

ARPAT

hPreso3 (856) ESVDDVCYYDREPYLALGAPSPTVSSLQDMQGEPGLLETKALGLLAPLRETKSTNPASRVMEMEPETMETKSVIDSRVSSISAIRFRIDPNNKEN

SGVVP

QHQNTTYFLAQHLNKDSLLARKDLPFRIQSCAAQAVLTAPYSLGR

PDPNP

1001 1100

hPreso1 (973) DLPPKVVPSKQLLHSDHMEMEPETMETKSVTDYFSKLHMGSVAYSCTSKR

hPreso2 (868) SLQPIATGQSPGPPGARRKLPQSEGQVQGERTYSLAVHPALSPQLSEQKN

KSKLADGEGKAPP-----------NGNTTGKKQQGTKTAEMEEEA

KFG

hPreso3 (956) AASSSASTPHCSNPGSSGPDTAQARPSQ-ILPLSQDLDGIAPKEPTIEHGDSSFSLSSGDPNPDRACLAS----NPGLNNVSQGDTLELQLEPHV

LEMG

LSLLSPVPEDKGPGHTRAGLEMSLRAATSSLSEEQVSELRDNLPK

VRLS

1101 1200

hPreso1 (1062) TVSSRDSQHLSTFNLERTAFRKDSQRWYVATEGGMAE----KS--GLEAA

hPreso2 (968) PKLILDPKSSVTPAIISAALQQVVHNKSLVTAGGALGNPPSRGERRLEAS

TG------KTFPRASGLGAREAEGKEEGAPDGETSDGSGLGQGDR

hPreso3 (1052) LESFCTNHIQETAPKYTEPLLSPRDEPRSDECGINPGEK-IASIPTKEEPQGQLSLERDREVTNKNGTNVFQEESRKDSGDSPGDVSNNVSQTLD

MGRPEVSMMSSSASKNLKFKISPSAPETSWNSQHQLGAEVSSSPR

D-domain

E

Homer site

MDVFS LSS

LDS-----

-----

L

L

L

L

L R

R

R

R

----

GLD

LCL

-----

LE

LE

SG

Q

E

Figure S2


1201 1300

hPreso1 (1150) TCASSAKDLDNPEDADSSTCDHPSKLPEA--DESVARLCDYHLAKRMSSL

hPreso2 (1068) RADSLHLSQQEDSLPVQNFPPKSYLLRTS--RESVGKQATGEVAGKGGPV

QSEGHFSLQ--SS-QGSSVDAGCGTGSS------------G----

hPreso3 (1152) GKIVTSLSLDAPVTGTEQIPPHPPRDPQGQSREPPGQGCQAQEQKLFVELDLDPDFFLGKQTVSPAVPPEGIKAEAPNHVTGQDIAPRDSPEWVC

GGKPTLQKQGTISSQGEKAQLESTPKRSKLEETSLVPRATYPMAL

1301 1400

hPreso1 (1229) ---SACATPVESPLCPSLGKHLIPDASGKGVNYIPSEE-----RAPGLPN

hPreso2 (1166) ---PSCQSRSHSPSCQPHGHSPSSQSRGQSPSCQPRGQSPLRSQAASRQV

HGATFKELHPQTEGMCPRMTVPALHTAINTEPLFGTLRDGCHRLP

KIKET

hPreso3 (1252) SLPEPLPCPQEDPHLETSNHCLLSEGKSDSSSICLSAEKSFLCFAPESHPEVSASLRVATSLGFAGMNEMVAPRIGMDQCSCQFSYATCFRGPQP

E----

STMPSRKLETTLNGAHSTSEGPAKPKSSRGPFRLRNLFSATFPTR

KET

1401 1500

hPreso1 (1316) TV------------------------------------------------

hPreso2 (1260) DERQAQLQKVKQYELEFLEELLKPPSQGELPGTEYLQPPAPGRCSCQLRS

---------------------------------------------

hPreso3 (1352) TEEEDR--DLEAHPMAPLTS---PPSAGSPVVLPWRPARAHSCTTAPLSR KSHIWPEYCSRALRQLKATPASTPEGFIQLMESLLELQDILETSW

VGNK

SPVQQGPGMSREQRRSCDCKRICRGGRPQATQTPVPSLRGRERDR

LPSQ

1501 1600

hPreso1 (1316) --------------------------------------------------

hPreso2 (1360) RQPEAGPGVSLSSPINVQRIRSTSLESRECRSDPESGVSCLTTCASGGEC

---------------------------------------------

hPreso3 (1443) HPPEKCTWHFTESRSRLCMGSQKLLSSCRHVIRMDQSPEEMQGAVRDTFQ HLVQLAGLCFQFTDCSRCSARHREAAGNLRDVVYTYHQFIEAAKS

LGAPNYRKLMRRYSISELDQGDRASLTSDVYPHPPLGMLPREAKE

1601 1700

hPreso1 (1316) --------------------------------------------------

hPreso2 (1460) PIALGPKSRSLESPTLGDPSYVQVAPETKGPRQMAVFSLPEEVYRKPAEL

---------------------------------------------

hPreso3 (1541) YHDLSVKLLARQCTALTAAVFCLTQKFRASTAL----------------- ---------------------------------------------

DEDSESSKCCSIRYCFYYRKCDMADDASDGKDELSYSIPMKILPG

1701 1800

hPreso1 (1316) --------------------------------------------------

hPreso2 (1560) QVVPVVSRTLQVLDAATCSSSSPEASRTQEIDLRVSTFEGSLAKINALRA

---------------------------------------------

hPreso3 (1541) -----------------------------------------------------------------------------------------------HAYGLPDGFLAARLDTNELLTVLRQCVASPEARAPKPYVSQISEY

1801 1900hPreso1 (1316) --------------------------------------------------

hPreso2 (1660) LKFKELRASCRRVANVDKSPTHMLAAITGSFQVLSSLIETFVRLVFIVRS

---------------------------------------------

hPreso3 (1541) -----------------------------------------------------------------------------------------------

EAQRQELLAKVEEVVRNYTFLLRAAEESTARNLNQQQQQQQQQQQ

1901 1950

hPreso1 (1316) ---------------------------------------------

hPreso3 (1541) ---------------------------------------------hPreso2 (1760) QQQQQQQQQQQVAAAAGAATEHPPGSPTSATVMSTFTHSLKTLIK

FLTDV

ISSPA

APTGS

-----

FNPEP

QS---

QK

G

V

-----

TCERG

VEASL

-----

-----

-----

-----

-----

-----

-----

MKLDE

KLELA

QQQQQ

Supplementary Figure 2: The amino acid sequence alignment of human Preso family. Red residues shaded in yellow are identical in all the predicted proteins, dark blue residues shaded in light blue are identical in > 50% of the predicted proteins, similar residues are shown in black shaded in green. D–domain and Homer binding site are indicated.


Preso1

Preso3

Preso2

Supplementary Figure 3: Preso family expression patterns by in situ hybridization. 1Kb C–terminal coding region of each gene was used for antisense and sense probes that were labeled with [35S].

Figure S3


aMyc–Preso1: + +Myc–Preso2: + +Myc–Preso3: + +Myc–Homer1c: + + +

Lysate

IP: Homer1c

Blot with anti–myc

mGluR2: + + + +Myc–Preso1: + +

mGluR4: + + + + Myc–Preso1: + +

HA–mGluR5: + + + +Myc–Preso1: + +

anti–HA

anti–Myc

anti–mGluR2

anti–Myc

anti–mGluR4

anti–Myc

b

Lysate IP: anti–Preso1

Lysate IP: anti–Preso1 Lysate IP: anti–Preso1c d

98KD

49KD

98KD

49KD

188KD

98KD

188KD

98KD

188KD

98KD

pS–mGluR

mGluR5 50 KD

50 KD

mGluR5 C–term:

λ–Phosphatase: – – + +S11

26A

WT S11

26A

WT

e

Figure S4


Supplementary Figure 4: Preso family: co–IP assays with Homer and mGluRs. a, Preso1 and Preso2 co–IP with Homer1c, but Preso3 does not. Myc–Homer1 and Myc–Presos were transfected into HEK293T cells. Detergent lysates of the cells were incubated with anti–Homer1c antibody and then analyzed by Western blotting with anti–Myc antibody. b, mGluR5 co–IPs with Preso1. Myc–Preso1 and HA–mGluR5 were transfected into HEK293T cells. Detergent lysates were incubated with anti–Preso1 antibody and blotted with anti–Myc and anti–HA antibody. c,mGluR2 does not co–IP with Preso1. Myc–Preso1 and mGluR2 were transfectedinto HEK293T cells. Detergent lysates were incubated with anti–Preso1 antibody and precipitates analyzed by Western blotting with anti–Myc and anti–mGluR2 antibody. d, mGluR4 does not co–IP with Preso1. Myc–Preso1 and mGluR4 were transfected into HEK293T cells. Detergent lysates were incubated with anti–Preso1 antibody and precipitates analyzed by Western blotting with anti–Myc and anti–mGluR4 antibody. e, Characterization of mGluR5 phosphorylation antibody. The phosphorylation site–specific anti–mGluR5–pS1126 antibody detects wild–type mGluR5 C–terminus from transfected HEK293 cells, but not mGluR5(S1126A) mutant. λ–phosphatase treatment of the immunoblot abolishes reactivity of wild–type mGluR5 C–terminus. A phosphorylation–independent anti–mGluR5 C–terminus antibody is used to detect expression of wild–type and mutant mGluR5 C–terminus.


EX2 EX3 EX490kb

Nhe I NheIShort Arm Long Arm

PGK-neo EX3

EX3

LoxP LoxPfrtfrt

Figure S5

353 bp517 bp

245 bp409 bp

+/+ +/– –/– +/+ +/– –/– +/+ +/– –/– +/+ +/– –/–

Cortex Cerebellum Cortex Cerebellumb

a

Preso1locus

Preso1 protein

Targeting vector

EX2 EX3 EX4

90kbPGK-neo

LoxP LoxPfrtfrt

EX2 EX4

90kbLoxPCre-recombinase expression

Preso1 floxedallele

Preso1- allele

c

Preso1

Actin

Preso1

Actin

WT

d

188KD

98KD

Cortex Hippocampus Striatum CerebellumW1 W2 K1 K2 W1 W2 K1 K2 W1 W2 K1 K2 W1 W2 K1 K2

Homer1

Homer2

Homer3

GluN1

GluA1

GluA2/3

Actin

e

WW PDZ FERMRA Homer Ligand PDZ Ligand

ETTVPPPGFRD

188KD

98KD

38KD

38KD

49KD

49KD

49KD

98KD

98KD

98KD

38KD

Preso1–/–

WT Preso1–/–


Supplementary Figure 5: PKAP1 knockout mice generation. a, Schematic representation of the Preso1 gene targeting strategy. The relevant portion of the Preso1locus Exon 3 was inserted in the LoxP/PGK–neo cassette to make a conditional knockout. CMV–CRE mice were employed to generate Preso1–/– mice. b, RT–PCR analysis after CMV–CRE expression. Two independent primer sets in different exons were used. c,Western blot analysis shows absence of Preso1 immunoreactivity in Preso1–/– mouse brain. d, Western blot analysis shows absence of Preso1 immunoreactivity in Preso1–/– cortical neurons. e, Western blot analysis showing no significant difference of Homer1, Homer2, Homer3, NMDA receptor GluN1, GluA1 and GluA2/3 protein expression between 8–week–old WT and Preso1–/– mouse brain. W: WT; K: Preso1–/–.


a bWT

WT/ MPEP

0-10min 10-60min0

50

100

150

200

250300

350

Dur

atio

n of

resp

onse

(s)

***

Figure S6

-10 0 10 20 30 40 50 60-20

0

20

40

60

80

100

Dur

atio

n of

resp

onse

(s)

Time after formalin injection (min)

400Grm5–/– / MPEP

Grm5–/–WT

WT/ MPEPGrm5–/– / MPEP

Grm5–/–

Supplementary Figure 6: Grm5–/– mice show reduced response to formalin–induced inflammatory pain. a, b, Formalin–induce inflammatory pain in Grm5–/– mice. a, The duration of behavioral responses to hind paw formalin injection in 5–min intervals in Grm5–/–mice and their WT littermates with or without MPEP (30mg/kg, i.p.) pre–injection. b, Results from a grouped into two phases. *P < 0.05, **P < 0.01, n = 7–11 for each group.


Figure S7

WT

0 200 400 600 800 1000

0

2

4

6

8

10

Spik

e nu

mbe

r

Injected current (nA)

WTa

b

20 ms

20 m

V

300 nA

Preso1–/–

Preso1–/–

Supplementary Figure 7: Excitability of DRG neurons is not different between WT and Preso1–/– mice. The small–diameter DRG neurons were cultured and injected with depolarizing currents stepwise from 100 to 900 nA with 100 nA interval. Each injected current lasted 200 ms and was separated by an interval of 4 s. The excitability was evaluated by the number of action potentials. WT and Preso1–/– DRG neurons do not show a significant difference of excitability. Eight neurons from 3 WT mice and 10 neurons from 3 Preso1–/– littermates were recorded.


Figure S8

ba

dc

fe

**

**

*WT

0-10min 10-60min0

100

200

300

400

500

600

**

Dur

atio

n of

resp

onse

(s)

WT

700

800

-10 0 10 20 30 40 50 60-20

020406080

100120140160180

Dur

atio

n of

resp

onse

(s)


*

WT

0-10min 10-60min0

100

200

300

400

500

600

**D

urat

ion

of re

spon

se (s

)

WT

-10 0 10 20 30 40 50 60-20

0

20

40

60

80

100

120

140

Dur

atio

n of

resp

onse

(s)


700

-10 0 10 20 30 40 50 60-20

0

20

40

60

80

100

120

Dur

atio

n of

resp

onse

(s)

Time after formalin injection (min)0-10min 10-60min

0

50

100

150

200

250

300

350

400 *

Dur

atio

n of

resp

onse

(s)

WT WT

Homer2–/–Homer3–/– Homer2–/–Homer3–/–

Grm5R/RGrm5R/R

Homer1a–/–Homer1a–/–


Supplementary Figure 8: Formalin–induced inflammatory pain responses inHomer2–/–Homer3–/– mice, Grm5R/R mice and Homer1a–/–mice. a, b, Formalin–induce inflammatory pain is increased in Homer2–/–Homer3–/– mice. a, The duration of behavioral responses to hind paw formalin injection in 5–min intervals in Homer2–/–Homer3–/– mice and their WT controls. b, Results from a, grouped into two phases. *P < 0.05, **P < 0.01, n = 12 and 8 for WT and Homer2–/–Homer3–/– mice. c, d,Formalin–induced inflammatory pain is increased in Grm5R/R mice. c, The duration of behavioral responses to hind paw formalin injection in 5–min intervals in Grm5R/Rmice and their WT littermates. d, Results from c grouped into two phases. *P < 0.05, **P < 0.01, n = 8 for each group. e, f, Formalin–induce inflammatory pain is reduced in Homer1a–/– mice. e, The duration of behavioral responses to hind paw formalin injection in 5–min intervals in Homer1a–/– mice and their WT littermates. f, Results from e, grouped into two phases. *P < 0.05, n = 9 for each group.


Figure S9

b cHA–Preso1: + F806R + +HA–Homer1c: + + G89N W24A

Lysate

IP: anti-Preso1

49KD

98KD

62KD

188KD

Homer1c

Preso1

Homer1c

Preso1

28KD

38KD

49KD

98KD

62KD

188KD

28KD

38KD 49KD

98KD

62KD

188KD

28KD

38KD

49KD

98KD

62KD

188KD

38KD

49KD

98KD

62KD

188KD

28KD

38KD

49KD

98KD

62KD

188KD

98KD

188KD

Homer3

IP: anti–Preso1

mGluR1

Lysate PI IP

IP3R

Shank

PSD95

Preso1

Supplementary Figure 9: Full length western blot for Figure 1. Samples were loaded on a 4–12% gel and blotted for the antibodies indicated in the figure. Dotted lines indicated that the bands were used for inclusion in Figure 1.


Figure S10a b

c e

98KD

62KD

188KD

Preso1 / Lysate

IP: anti–Preso1

HA–Preso1:

Myc–mGluR5: + + + + + + F1128R FL

ΔPDZ

ΔW

W

ΔFE

RM

mGluR5 / co–IP

mGluR5 / Lysate

Preso1 / IP

F806

R

F806

R

98KD

188KD

98KD

188KD

62KD

98KD

188KD

Myc–Preso1FERM: +

HA–mGluR5: + +

Preso1FERM / Lysate

IP: anti-Myc

mGluR5 / co–IP

mGluR5 / Lysate

Preso1FERM / IP

49KD

98KD

62KD

188KD

28KD

38KD

49KD

98KD

62KD

188KD

28KD

38KD

YVFYV FR W

THA–mGluR5:

IP: anti–Myc

98KD

188KD

98KD

188KD

188KD

188KDPreso1 / Lysate

mGluR5 / co–IP

mGluR5 / Lysate

Preso1 / IP

Myc–Preso1: + + + +HA–mGluR5:

Myc–Preso1: + + + +W

T1~

1020

1~92

0

IP: anti–Myc

98KD

188KD

188KD

98KD

Preso1 / Lysate

mGluR5 / co–IP mGluR5 / Lysate

Preso1 / IP

62KD

WT

1~10

20

1~92

0


Supplementary Figure 10: Full length western blot for Figure 2. Samples were loaded on a 4–12% gel and blotted for the antibodies indicated in the figure. Dotted lines indicated that the bands were used for inclusion in Figure 2.


Figure S11

a b

mGluR5

Homer1c:

Preso1

Homer1c

Lysate

+ ++ +

+

Homer1cIP

+ ++ +

+

Lysate

+ ++ +

+

pS–mGluR

188KD

98KD

mGluR5WT:

Preso1:

49KD

98KD

188KD

28KD

38KD

mGluR5

Homer1c:

Preso1

Homer1c

Lysate

+ ++ +

+

Homer1cIP+ ++ +

+

Lysate

+ +

+ +

Homer1cIP+ +

+ +++

mGluR5WT:mGluR5TSAA:

Preso1FR:

188KD

98KD

49KD

98KD

188KD

28KD

38KD

62KD

62KD

Supplementary Figure 11: Full length western blot for Figure 3. Samples were loaded on a 4–12% gel and blotted for the antibodies indicated in the figure. mGluR5 dimers were used for mGluR5 band quantification. Dotted lines indicated that the bands were used for inclusion in Figure 3.


Figure S12

a b c

eg

d

f

HA–mGluR5:

HA–CDK5/P35:

HA–MEK DD:

+ + ++

+

98KD

188KD

38KD

98KD

188KD

28KD

49KD

pS–mGluR

CDK5

mGluR5

P35

MEK DD

pS–mGluR

mGluR5

Con

trol

UO

126

Purv

alan

olA

98KD

188KD

98KD

188KD

+ + + +

Preso1

CDK5

+ +HA–CDK5:HA–Preso1:

IP: anti–Preso1 Lysate

98KD

28KD

38KD

188KD

Preso1

IP: anti–Preso1 Lysate

ERK1

+ + + +HA–ERK1:+ +HA–Preso1:

98KD

38KD

49KD

188KD

HA–mGluR5:

HA–Preso1:

HA–ERK1:

IP: anti–mGluR5 Lysate

Preso1mGluR5 monomer

mGluR5 dimer

ERK1

+ ++ +

+ + +

+ ++ +

+ + +

98KD

188KD

38KD

49KD

IP: anti–CDK5

Lysate PI IP

CDK5

Preso1

IP: anti–ERK

ERK1/2

Preso1

Lysate PI IP

49KD

98KD

62KD

188KD

38KD

28KD

38KD

49KD

98KD

62KD

188KD

28KD

38KD



Figure S13

mGluR5 / Lysate

mGluR5 / co–IP

Homer / IP

Preso1 / Lysate

pS–mGluR

Cx Sc

WT Preso1–/– WT Preso1–/–

49KD

98KD

188KD

38KD

98KD

188KD

98KD

188KD

98KD

62KD

188KD

mGluR5 / IP

ERK1/2 / co–IP

ERK1/2 / Lysate

mGluR5 / Lysate

WT Preso1–/–

49KD

38KD

49KD

38KD

98KD

188KD

98KD

188KD

a

b

c

d

Ctl BD Ctl BD

mGluR5 / Lysate

mGluR5 / co–IP

Homer / IP

Ctl DH Ctl DH

Actin / Lysate

pS–mGluR


49KD

98KD

188KD

38KD

98KD

188KD

98KD

188KD

49KD

38KD

mGluR5 / Total

mGluR5 / Surface

Actin / Surface

Actin / Total

Ctl D5 Ctl D5 Ctl D30 Ctl D30


49KD

38KD

98KD

188KD

98KD

188KD

49KD

38KD


supplementary information · supplementary information preso1 dynamically regulates group i...

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