Reviewed, UniProtKB/Swiss-Prot O75643 (U520_HUMAN)

Names and origin

Protein names

Recommended name:
    U5 small nuclear ribonucleoprotein 200 kDa helicase
    EC=3.6.1.-
Alternative name(s):
    U5 snRNP-specific 200 kDa protein
      Short name=U5-200KD
    Activating signal cointegrator 1 complex subunit 3-like 1
    BRR2 homolog

Gene names

Name:	ASCC3L1
Synonyms:	HELIC2, KIAA0788

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	2136 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Putative RNA helicase involved in the second step of RNA splicing. May promote one or more conformational changes in the dynamic network of RNA-RNA interactions in the spliceosome. Appears to catalyze an ATP-dependent unwinding of U4/U6 RNA duplices. Ref.7
Subunit structure	U5 snRNP contains nine specific proteins with molecular weights of 40, 52, 100, 102, 110, 116, 200 and 220 kDa. Identified in the spliceosome C complex, at least composed of AQR, ASCC3L1, C19orf29, CDC40, CDC5L, CRNKL1, DDX23, DDX41, DDX48, DDX5, DGCR14, DHX35, DHX38, DHX8, EFTUD2, FRG1, GPATC1, HNRPA1, HNRPA2B1, HNRPA3, HNRPC, HNRPF, HNRPH1, HNRPK, HNRPM, HNRPR, HNRPU, KIAA1160, KIAA1604, LSM2, LSM3, MAGOH, MORG1, PABPC1, PLRG1, PNN, PPIE, PPIL1, PPIL3, PPWD1, PRPF19, PRPF4B, PRPF6, PRPF8, RALY, RBM22, RBM8A, RBMX, SART1, SF3A1, SF3A2, SF3A3, SF3B1, SF3B2, SF3B3, SFRS1, SKIV2L2, SNRPA1, SNRPB, SNRPB2, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF, SNRPG, SNW1, SRRM1, SRRM2, SYF2, SYNCRIP, TFIP11, THOC4, U2AF1, WDR57, XAB2 and ZCCHC8.
Subcellular location	Nucleus. Ref.7
Domain	Composed of two similar domains.
Sequence similarities	Belongs to the helicase family. SKI2 subfamily. Contains 2 helicase ATP-binding domains. Contains 2 helicase C-terminal domains.

Ontologies

Keywords
Biological process	mRNA processing mRNA splicing
Cellular component	Nucleus Spliceosome
Coding sequence diversity	Alternative splicing Polymorphism
Domain	Repeat
Ligand	ATP-binding Nucleotide-binding
Molecular function	Helicase Hydrolase
PTM	Phosphoprotein Ubl conjugation
Technical term	3D-structure Direct protein sequencing
Gene Ontology (GO)
Biological process	cis assembly of pre-catalytic spliceosome Ref.7 Inferred by curator. Source: HGNC
Cellular component	snRNP U5 Ref.7 Inferred from direct assay. Source: HGNC
Molecular function	ATP binding Ref.7 Inferred by curator. Source: HGNC ATP-dependent helicase activity Ref.7 Inferred from direct assay. Source: HGNC nucleic acid binding Inferred from electronic annotation. Source: InterPro protein binding Inferred from physical interaction. Source: IntAct
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
CD2BP2	O95400	1	EBI-1045395,EBI-768015
MCC	P23508	1	EBI-1045395,EBI-307531
PRKAB1	Q9Y478	1	EBI-1045395,EBI-719769
RNPS1	Q15287	1	EBI-1045395,EBI-395959
SNRPB	P14678	1	EBI-1045395,EBI-372458
WDR57	Q96DI7	2	EBI-1045395,EBI-538492
YWHAG	P61981	1	EBI-1045395,EBI-359832

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: O75643-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: O75643-2)

The sequence of this isoform differs from the canonical sequence as follows:
     561-2071: Missing.

Notes: No experimental confirmation available.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 2136	2136	U5 small nuclear ribonucleoprotein 200 kDa helicase		PRO_0000102087
Regions
	Domain	490 – 673	184	Helicase ATP-binding 1
	Domain	684 – 921	238	Helicase C-terminal 1
	Domain	1337 – 1512	176	Helicase ATP-binding 2
	Domain	1545 – 1753	209	Helicase C-terminal 2
	Nucleotide binding	503 – 510	8	ATP Potential
	Nucleotide binding	1350 – 1357	8	ATP Potential
	Motif	615 – 618	4	DEIH box
	Motif	1454 – 1457	4	DEVH box
Amino acid modifications
	Modified residue	26	1	Phosphoserine Ref.15
	Modified residue	225	1	Phosphoserine Ref.15 Ref.10 Ref.11 Ref.13 Ref.14 Ref.16
	Modified residue	756	1	Phosphoserine Ref.10
	Modified residue	922	1	Phosphotyrosine Ref.12
	Modified residue	924	1	Phosphotyrosine Ref.12
	Modified residue	926	1	Phosphotyrosine Ref.12
	Modified residue	1056	1	Phosphoserine Ref.11
	Modified residue	2131	1	Phosphothreonine Ref.15
	Modified residue	2133	1	Phosphoserine Ref.15
	Modified residue	2135	1	Phosphoserine Ref.15
	Cross-link	944		Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO)
	Cross-link	971		Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO)
	Cross-link	1071		Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO)
	Cross-link	1199		Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO)
	Cross-link	2091		Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO)
Natural variations
	Alternative sequence	561 – 2071	1511	Missing in isoform 2.		VSP_026622
	Natural variant	1736	1	F → L in a colorectal cancer sample; somatic mutation. Ref.17		VAR_035943
Experimental info
	Sequence conflict	588	1	C → F in AAH65924. Ref.6
	Sequence conflict	613	1	I → V in CAA94089. Ref.5
	Sequence conflict	802	1	A → G in CAA94089. Ref.5
	Sequence conflict	840	1	R → H in BAB14906. Ref.2
	Sequence conflict	1087	1	S → L in AAS78571. Ref.1
	Sequence conflict	1322	1	Q → R in BAB14906. Ref.2
	Sequence conflict	1371	1	S → N in CAA94089. Ref.5
	Sequence conflict	1383 – 1386	4	EALA → RLWQ in CAA94089. Ref.5
	Sequence conflict	1476	1	Y → N in BAB14906. Ref.2
	Sequence conflict	1547	1	Y → F in CAA94089. Ref.5
	Sequence conflict	1667	1	Q → L in CAA94089. Ref.5
	Sequence conflict	1956	1	K → E in CAA94089. Ref.5
	Sequence conflict	1961 – 1962	2	KQ → RR in CAA94089. Ref.5
	Sequence conflict	1965 – 1971	7	HFTSEHI → PFPSGLF in CAA94089. Ref.5
	Sequence conflict	2031	1	S → R in BAB14906. Ref.2
	Sequence conflict	2065	1	W → L in AAH65924. Ref.6
	Sequence conflict	2101 – 2104	4	AHNY → GRHN in CAA94089. Ref.5

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified December 7, 2004. Version 2. Checksum: 3F3811BDCCC9DDB7	FASTA	2,136	244,508
	10 20 30 40 50 60 MADVTARSLQ YEYKANSNLV LQADRSLIDR TRRDEPTGEV LSLVGKLEGT RMGDKAQRTK 70 80 90 100 110 120 PQMQEERRAK RRKRDEDRHD INKMKGYTLL SEGIDEMVGI IYKPKTKETR ETYEVLLSFI 130 140 150 160 170 180 QAALGDQPRD ILCGAADEVL AVLKNEKLRD KERRKEIDLL LGQTDDTRYH VLVNLGKKIT 190 200 210 220 230 240 DYGGDKEIQN MDDNIDETYG VNVQFESDEE EGDEDVYGEV REEASDDDME GDEAVVRCTL 250 260 270 280 290 300 SANLVASGEL MSSKKKDLHP RDIDAFWLQR QLSRFYDDAI VSQKKADEVL EILKTASDDR 310 320 330 340 350 360 ECENQLVLLL GFNTFDFIKV LRQHRMMILY CTLLASAQSE AEKERIMGKM EADPELSKFL 370 380 390 400 410 420 YQLHETEKED LIREERSRRE RVRQSRMDTD LETMDLDQGG EALAPRQVLD LEDLVFTQGS 430 440 450 460 470 480 HFMANKRCQL PDGSFRRQRK GYEEVHVPAL KPKPFGSEEQ LLPVEKLPKY AQAGFEGFKT 490 500 510 520 530 540 LNRIQSKLYR AALETDENLL LCAPTGAGKT NVALMCMLRE IGKHINMDGT INVDDFKIIY 550 560 570 580 590 600 IAPMRSLVQE MVGSFGKRLA TYGITVAELT GDHQLCKEEI SATQIIVCTP EKWDIITRKG 610 620 630 640 650 660 GERTYTQLVR LIILDEIHLL HDDRGPVLEA LVARAIRNIE MTQEDVRLIG LSATLPNYED 670 680 690 700 710 720 VATFLRVDPA KGLFYFDNSF RPVPLEQTYV GITEKKAIKR FQIMNEIVYE KIMEHAGKNQ 730 740 750 760 770 780 VLVFVHSRKE TGKTARAIRD MCLEKDTLGL FLREGSASTE VLRTEAEQCK NLELKDLLPY 790 800 810 820 830 840 GFAIHHAGMT RVDRTLVEDL FADKHIQVLV STATLAWGVN LPAHTVIIKG TQVYSPEKGR 850 860 870 880 890 900 WTELGALDIL QMLGRAGRPQ YDTKGEGILI TSHGELQYYL SLLNQQLPIE SQMVSKLPDM 910 920 930 940 950 960 LNAEIVLGNV QNAKDAVNWL GYAYLYIRML RSPTLYGISH DDLKGDPLLD QRRLDLVHTA 970 980 990 1000 1010 1020 ALMLDKNNLV KYDKKTGNFQ VTELGRIASH YYITNDTVQT YNQLLKPTLS EIELFRVFSL 1030 1040 1050 1060 1070 1080 SSEFKNITVR EEEKLELQKL LERVPIPVKE SIEEPSAKIN VLLQAFISQL KLEGFALMAD 1090 1100 1110 1120 1130 1140 MVYVTQSAGR LMRAIFEIVL NRGWAQLTDK TLNLCKMIDK RMWQSMCPLR QFRKLPEEVV 1150 1160 1170 1180 1190 1200 KKIEKKNFPF ERLYDLNHNE IGELIRMPKM GKTIHKYVHL FPKLELSVHL QPITRSTLKV 1210 1220 1230 1240 1250 1260 ELTITPDFQW DEKVHGSSEA FWILVEDVDS EVILHHEYFL LKAKYAQDEH LITFFVPVFE 1270 1280 1290 1300 1310 1320 PLPPQYFIRV VSDRWLSCET QLPVSFRHLI LPEKYPPPTE LLDLQPLPVS ALRNSAFESL 1330 1340 1350 1360 1370 1380 YQDKFPFFNP IQTQVFNTVY NSDDNVFVGA PTGSGKTICA EFAILRMLLQ SSEGRCVYIT 1390 1400 1410 1420 1430 1440 PMEALAEQVY MDWYEKFQDR LNKKVVLLTG ETSTDLKLLG KGNIIISTPE KWDILSRRWK 1450 1460 1470 1480 1490 1500 QRKNVQNINL FVVDEVHLIG GENGPVLEVI CSRMRYISSQ IERPIRIVAL SSSLSNAKDV 1510 1520 1530 1540 1550 1560 AHWLGCSATS TFNFHPNVRP VPLELHIQGF NISHTQTRLL SMAKPVYHAI TKHSPKKPVI 1570 1580 1590 1600 1610 1620 VFVPSRKQTR LTAIDILTTC AADIQRQRFL HCTEKDLIPY LEKLSDSTLK ETLLNGVGYL 1630 1640 1650 1660 1670 1680 HEGLSPMERR LVEQLFSSGA IQVVVASRSL CWGMNVAAHL VIIMDTQYYN GKIHAYVDYP 1690 1700 1710 1720 1730 1740 IYDVLQMVGH ANRPLQDDEG RCVIMCQGSK KDFFKKFLYE PLPVESHLDH CMHDHFNAEI 1750 1760 1770 1780 1790 1800 VTKTIENKQD AVDYLTWTFL YRRMTQNPNY YNLQGISHRH LSDHLSELVE QTLSDLEQSK 1810 1820 1830 1840 1850 1860 CISIEDEMDV APLNLGMIAA YYYINYTTIE LFSMSLNAKT KVRGLIEIIS NAAEYENIPI 1870 1880 1890 1900 1910 1920 RHHEDNLLRQ LAQKVPHKLN NPKFNDPHVK TNLLLQAHLS RMQLSAELQS DTEEILSKAI 1930 1940 1950 1960 1970 1980 RLIQACVDVL SSNGWLSPAL AAMELAQMVT QAMWSKDSYL KQLPHFTSEH IKRCTDKGVE 1990 2000 2010 2020 2030 2040 SVFDIMEMED EERNALLQLT DSQIADVARF CNRYPNIELS YEVVDKDSIR SGGPVVVLVQ 2050 2060 2070 2080 2090 2100 LEREEEVTGP VIAPLFPQKR EEGWWVVIGD AKSNSLISIK RLTLQQKAKV KLDFVAPATG 2110 2120 2130 AHNYTLYFMS DAYMGCDQEY KFSVDVKEAE TDSDSD
	Isoform 2. Checksum: EDC83DE90411A495		625	71,472
	10 20 30 40 50 60 MADVTARSLQ YEYKANSNLV LQADRSLIDR TRRDEPTGEV LSLVGKLEGT RMGDKAQRTK 70 80 90 100 110 120 PQMQEERRAK RRKRDEDRHD INKMKGYTLL SEGIDEMVGI IYKPKTKETR ETYEVLLSFI 130 140 150 160 170 180 QAALGDQPRD ILCGAADEVL AVLKNEKLRD KERRKEIDLL LGQTDDTRYH VLVNLGKKIT 190 200 210 220 230 240 DYGGDKEIQN MDDNIDETYG VNVQFESDEE EGDEDVYGEV REEASDDDME GDEAVVRCTL 250 260 270 280 290 300 SANLVASGEL MSSKKKDLHP RDIDAFWLQR QLSRFYDDAI VSQKKADEVL EILKTASDDR 310 320 330 340 350 360 ECENQLVLLL GFNTFDFIKV LRQHRMMILY CTLLASAQSE AEKERIMGKM EADPELSKFL 370 380 390 400 410 420 YQLHETEKED LIREERSRRE RVRQSRMDTD LETMDLDQGG EALAPRQVLD LEDLVFTQGS 430 440 450 460 470 480 HFMANKRCQL PDGSFRRQRK GYEEVHVPAL KPKPFGSEEQ LLPVEKLPKY AQAGFEGFKT 490 500 510 520 530 540 LNRIQSKLYR AALETDENLL LCAPTGAGKT NVALMCMLRE IGKHINMDGT INVDDFKIIY 550 560 570 580 590 600 IAPMRSLVQE MVGSFGKRLA KSNSLISIKR LTLQQKAKVK LDFVAPATGA HNYTLYFMSD 610 620 AYMGCDQEYK FSVDVKEAET DSDSD

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"The network of protein-protein interactions within the human U4/U6.U5 tri-snRNP." Liu S., Rauhut R., Vornlocher H.-P., Luehrmann R. RNA 12:1418-1430(2006) [PubMed: 16723661] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[2]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed: 14702039] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 264-2136 (ISOFORM 1). Tissue: Cerebellum and Placenta.
[3]	"Prediction of the coding sequences of unidentified human genes. XI. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro." Nagase T., Ishikawa K., Suyama M., Kikuno R., Miyajima N., Tanaka A., Kotani H., Nomura N., Ohara O. DNA Res. 5:277-286(1998) [PubMed: 9872452] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 111-2136 (ISOFORM 1). Tissue: Brain.
[4]	"Construction of expression-ready cDNA clones for KIAA genes: manual curation of 330 KIAA cDNA clones." Nakajima D., Okazaki N., Yamakawa H., Kikuno R., Ohara O., Nagase T. DNA Res. 9:99-106(2002) [PubMed: 12168954] [Abstract] Cited for: SEQUENCE REVISION.
[5]	"The HeLa 200 kDa U5 snRNP-specific protein and its homologue in Saccharomyces cerevisiae are members of the DEXH-box protein family of putative RNA helicases." Lauber J., Fabrizio P., Teigelkamp S., Lane W.S., Hartmann E., Luehrmann R. EMBO J. 15:4001-4015(1996) [PubMed: 8670905] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 436-2136, PROTEIN SEQUENCE OF 672-690; 1200-1213; 1295-1317; 1326-1338 AND 1717-1728. Tissue: Fetal brain.
[6]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 316-2136. Tissue: Placenta and Skin.
[7]	"The human U5-200kD DEXH-box protein unwinds U4/U6 RNA duplices in vitro." Laggerbauer B., Achsel T., Luehrmann R. Proc. Natl. Acad. Sci. U.S.A. 95:4188-4192(1998) [PubMed: 9539711] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION.
[8]	"Purification and characterization of native spliceosomes suitable for three-dimensional structural analysis." Jurica M.S., Licklider L.J., Gygi S.P., Grigorieff N., Moore M.J. RNA 8:426-439(2002) [PubMed: 11991638] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY, IDENTIFICATION IN THE SPICEOSOMAL C COMPLEX.
[9]	"A proteomic study of SUMO-2 target proteins." Vertegaal A.C.O., Ogg S.C., Jaffray E., Rodriguez M.S., Hay R.T., Andersen J.S., Mann M., Lamond A.I. J. Biol. Chem. 279:33791-33798(2004) [PubMed: 15175327] [Abstract] Cited for: SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-944; LYS-971; LYS-1071; LYS-1199 AND LYS-2091, MASS SPECTROMETRY.
[10]	"Large-scale characterization of HeLa cell nuclear phosphoproteins." Beausoleil S.A., Jedrychowski M., Schwartz D., Elias J.E., Villen J., Li J., Cohn M.A., Cantley L.C., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 101:12130-12135(2004) [PubMed: 15302935] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-225 AND SER-756, MASS SPECTROMETRY. Tissue: Epithelium.
[11]	"Global, in vivo, and site-specific phosphorylation dynamics in signaling networks." Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M. Cell 127:635-648(2006) [PubMed: 17081983] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-225 AND SER-1056, MASS SPECTROMETRY. Tissue: Epithelium.
[12]	"Tyrosine phosphorylated Par3 regulates epithelial tight junction assembly promoted by EGFR signaling." Wang Y., Du D., Fang L., Yang G., Zhang C., Zeng R., Ullrich A., Lottspeich F., Chen Z. EMBO J. 25:5058-5070(2006) [PubMed: 17053785] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-922; TYR-924 AND TYR-926, MASS SPECTROMETRY.
[13]	"Phosphoproteome analysis of the human mitotic spindle." Nousiainen M., Sillje H.H.W., Sauer G., Nigg E.A., Koerner R. Proc. Natl. Acad. Sci. U.S.A. 103:5391-5396(2006) [