O43707 (ACTN4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Alpha-actinin-4

Alternative name(s):
F-actin cross-linking protein
Non-muscle alpha-actinin 4

Gene names

Name:

ACTN4

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	911 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	F-actin cross-linking protein which is thought to anchor actin to a variety of intracellular structures. This is a bundling protein. Probably involved in vesicular trafficking via its association with the CART complex. The CART complex is necessary for efficient transferrin receptor recycling but not for EGFR degradation.
Subunit structure	Homodimer; antiparallel By similarity. Binds TRIM3 at the N-terminus By similarity. Identified in a complex with CASK, IQGAP1, MAGI2, NPHS1, SPTAN1 and SPTBN1 By similarity. Identified in a mRNP granule complex, at least composed of ACTB, ACTN4, DHX9, ERG, HNRNPA1, HNRNPA2B1, HNRNPAB, HNRNPD, HNRNPL, HNRNPR, HNRNPU, HSPA1, HSPA8, IGF2BP1, ILF2, ILF3, NCBP1, NCL, PABPC1, PABPC4, PABPN1, RPLP0, RPS3, RPS3A, RPS4X, RPS8, RPS9, SYNCRIP, TROVE2, YBX1 and untranslated mRNAs. Component of the CART complex, at least composed of ACTN4, HGS/HRS, MYO5B and TRIM3. Interacts with BAIAP1 and PDLIM2. Ref.7
Subcellular location	Nucleus. Cytoplasm. Note: Localized in cytoplasmic mRNP granules containing untranslated mRNAs. Colocalizes with actin stress fibers. Nuclear translocation can be induced by the PI3 kinase inhibitor wortmannin or by cytochalasin D. Exclusively localized in the nucleus in a limited number of cell lines (breast cancer cell line MCF7, oral floor cancer IMC2, and bladder cancer KU7). Ref.11
Tissue specificity	Widely expressed.
Involvement in disease	Defects in ACTN4 are the cause of focal segmental glomerulosclerosis type 1 (FSGS1) [MIM:603278]. A renal pathology defined by the presence of segmental sclerosis in glomeruli and resulting in proteinuria, reduced glomerular filtration rate and edema. Renal insufficiency often progresses to end-stage renal disease, a highly morbid state requiring either dialysis therapy or kidney transplantation. Ref.15
Sequence similarities	Belongs to the alpha-actinin family. Contains 1 actin-binding domain. Contains 2 CH (calponin-homology) domains. Contains 2 EF-hand domains. Contains 4 spectrin repeats.
Sequence caution	The sequence AAC17470.1 differs from that shown. Reason: Frameshift at positions 19, 26, 124, 130, 589, 594, 787 and 806. The sequence BAA24447.1 differs from that shown. Reason: Erroneous initiation.

Ontologies

Keywords
Biological process	Protein transport Transport
Cellular component	Cytoplasm Nucleus
Disease	Disease mutation
Domain	Repeat
Ligand	Actin-binding Calcium
PTM	Acetylation Isopeptide bond Phosphoprotein Ubl conjugation
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	platelet activation Traceable author statement. Source: Reactome platelet degranulation Traceable author statement. Source: Reactome positive regulation of cellular component movement Inferred from direct assay Ref.1. Source: UniProtKB positive regulation of sodium:hydrogen antiporter activity Non-traceable author statement. Source: UniProtKB protein transport Inferred from electronic annotation. Source: UniProtKB-KW regulation of apoptotic process Non-traceable author statement. Source: UniProtKB
Cellular component	extracellular region Traceable author statement. Source: Reactome nucleus Inferred from direct assay Ref.1. Source: UniProtKB perinuclear region of cytoplasm Inferred from direct assay. Source: UniProtKB platelet alpha granule lumen Traceable author statement. Source: Reactome protein complex Inferred from direct assay. Source: UniProtKB pseudopodium Traceable author statement. Source: UniProtKB ribonucleoprotein complex Inferred from direct assay Ref.11. Source: UniProtKB
Molecular function	actin filament binding Inferred from direct assay. Source: UniProtKB calcium ion binding Inferred from electronic annotation. Source: InterPro integrin binding Traceable author statement. Source: UniProtKB nucleoside binding Inferred from direct assay. Source: UniProtKB protein homodimerization activity Traceable author statement. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
CTNNB1	P35222	6	EBI-351526,EBI-491549
TJP1	Q07157	4	EBI-351526,EBI-79553

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 911

911

Alpha-actinin-4

PRO_0000073440

Regions

Domain

1 – 269

269

Actin-binding

Domain

50 – 154

105

CH 1

Domain

163 – 269

107

CH 2

Repeat

293 – 403

111

Spectrin 1

Repeat

413 – 518

106

Spectrin 2

Repeat

528 – 639

112

Spectrin 3

Repeat

649 – 752

104

Spectrin 4

Domain

765 – 800

36

EF-hand 1

Domain

806 – 841

36

EF-hand 2

Calcium binding

778 – 789

12

1 Potential

Calcium binding

819 – 830

12

2 Potential

Region

177 – 192

16

Polyphosphoinositide (PIP2)-binding Potential

Compositional bias

19 – 26

8

Poly-Gly

Amino acid modifications

Modified residue

114

1

N6-acetyllysine Ref.13

Modified residue

214

1

N6-acetyllysine Ref.13

Modified residue

265

1

Phosphotyrosine Ref.9 Ref.10

Modified residue

417

1

N6-acetyllysine Ref.13

Modified residue

592

1

N6-acetyllysine Ref.13

Modified residue

625

1

N6-acetyllysine Ref.13

Cross-link

378

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) Ref.12

Natural variations

Natural variant

255

1

K → E in FSGS1. Ref.15
Corresponds to variant rs28939374 [ dbSNP | Ensembl ].

VAR_010378

Natural variant

259

1

T → I in FSGS1. Ref.15
Corresponds to variant rs28939375 [ dbSNP | Ensembl ].

VAR_010379

Natural variant

262

1

S → P in FSGS1. Ref.15
Corresponds to variant rs28939376 [ dbSNP | Ensembl ].

VAR_010380

Experimental info

Sequence conflict

60

1

C → S in AAC17470. Ref.3

Sequence conflict

164

1

S → L in AL047603. Ref.4

Sequence conflict

164

1

S → L in AU118403. Ref.4

Sequence conflict

276

1

T → TET in AAC17470. Ref.3

Sequence conflict

292 – 294

3

EHL → CSTS in AAC17470. Ref.3

Sequence conflict

359 – 360

2

TL → SV in AAC17470. Ref.3

Sequence conflict

476

1

I → S in AAC17470. Ref.3

Sequence conflict

526

1

I → II in AAC17470. Ref.3

Sequence conflict

536

1

R → P in AAC17470. Ref.3

Sequence conflict

645

1

Q → QQ in AAC17470. Ref.3

Sequence conflict

673 – 674

2

GR → A in AAC17470. Ref.3

Sequence conflict

850

1

A → T in AAC17470. Ref.3

Sequence conflict

891 – 893

3

AVP → GVR in AAC17470. Ref.3

Secondary structure

1

.

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911

Helix Strand Turn

Details...

Helix

47 – 64

18

Helix

65 – 67

3

Turn

74 – 80

7

Helix

82 – 92

11

Helix

105 – 120

16

Turn

121 – 123

3

Helix

131 – 135

5

Helix

139 – 153

15

Turn

154 – 157

4

Helix

165 – 177

13

Beta strand

187 – 189

3

Helix

190 – 192

3

Helix

196 – 205

10

Helix

207 – 209

3

Helix

212 – 214

3

Helix

220 – 234

15

Helix

243 – 248

6

Beta strand

249 – 251

3

Helix

254 – 267

14

Sequences

	Sequence		Length	Mass (Da)
	O43707 [UniParc]. Last modified February 21, 2001. Version 2. Checksum: 461580C3F22937D1	FASTA	911	104,854
	10 20 30 40 50 60 MVDYHAANQS YQYGPSSAGN GAGGGGSMGD YMAQEDDWDR DLLLDPAWEK QQRKTFTAWC 70 80 90 100 110 120 NSHLRKAGTQ IENIDEDFRD GLKLMLLLEV ISGERLPKPE RGKMRVHKIN NVNKALDFIA 130 140 150 160 170 180 SKGVKLVSIG AEEIVDGNAK MTLGMIWTII LRFAIQDISV EETSAKEGLL LWCQRKTAPY 190 200 210 220 230 240 KNVNVQNFHI SWKDGLAFNA LIHRHRPELI EYDKLRKDDP VTNLNNAFEV AEKYLDIPKM 250 260 270 280 290 300 LDAEDIVNTA RPDEKAIMTY VSSFYHAFSG AQKAETAANR ICKVLAVNQE NEHLMEDYEK 310 320 330 340 350 360 LASDLLEWIR RTIPWLEDRV PQKTIQEMQQ KLEDFRDYRR VHKPPKVQEK CQLEINFNTL 370 380 390 400 410 420 QTKLRLSNRP AFMPSEGKMV SDINNGWQHL EQAEKGYEEW LLNEIRRLER LDHLAEKFRQ 430 440 450 460 470 480 KASIHEAWTD GKEAMLKHRD YETATLSDIK ALIRKHEAFE SDLAAHQDRV EQIAAIAQEL 490 500 510 520 530 540 NELDYYDSHN VNTRCQKICD QWDALGSLTH SRREALEKTE KQLEAIDQLH LEYAKRAAPF 550 560 570 580 590 600 NNWMESAMED LQDMFIVHTI EEIEGLISAH DQFKSTLPDA DREREAILAI HKEAQRIAES 610 620 630 640 650 660 NHIKLSGSNP YTTVTPQIIN SKWEKVQQLV PKRDHALLEE QSKQQSNEHL RRQFASQANV 670 680 690 700 710 720 VGPWIQTKME EIGRISIEMN GTLEDQLSHL KQYERSIVDY KPNLDLLEQQ HQLIQEALIF 730 740 750 760 770 780 DNKHTNYTME HIRVGWEQLL TTIARTINEV ENQILTRDAK GISQEQMQEF RASFNHFDKD 790 800 810 820 830 840 HGGALGPEEF KACLISLGYD VENDRQGEAE FNRIMSLVDP NHSGLVTFQA FIDFMSRETT 850 860 870 880 890 900 DTDTADQVIA SFKVLAGDKN FITAEELRRE LPPDQAEYCI ARMAPYQGPD AVPGALDYKS 910 FSTALYGESD L

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Actinin-4, a novel actin-bundling protein associated with cell motility and cancer invasion." Honda K., Yamada T., Endo R., Ino Y., Gotoh M., Tsuda H., Yamada Y., Chiba H., Hirohashi S. J. Cell Biol. 140:1383-1393(1998) [PubMed: 9508771] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 4-911.
[2]	Erratum Honda K., Yamada T., Endo R., Ino Y., Gotoh M., Tsuda H., Yamada Y., Chiba H., Hirohashi S. J. Cell Biol. 143:276-276(1998)
[3]	"The human non-muscle alpha-actinin protein encoded by the ACTN4 gene suppresses tumorigenicity of human neuroblastoma cells." Nikolopoulos S.N., Spengler B.A., Kisselbach K., Evans A.E., Biedler J.L., Ross R.A. Oncogene 19:380-386(2000) [PubMed: 10656685] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Neuroblastoma.
[4]	"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]. Tissue: Placenta.
[5]	"The full-ORF clone resource of the German cDNA consortium." Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., Wiemann S., Schupp I. BMC Genomics 8:399-399(2007) [PubMed: 17974005] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-170. Tissue: Uterus.
[6]	"Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes." Kimura K., Wakamatsu A., Suzuki Y., Ota T., Nishikawa T., Yamashita R., Yamamoto J., Sekine M., Tsuritani K., Wakaguri H., Ishii S., Sugiyama T., Saito K., Isono Y., Irie R., Kushida N., Yoneyama T., Otsuka R. , Kanda K., Yokoi T., Kondo H., Wagatsuma M., Murakawa K., Ishida S., Ishibashi T., Takahashi-Fujii A., Tanase T., Nagai K., Kikuchi H., Nakai K., Isogai T., Sugano S. Genome Res. 16:55-65(2006) [PubMed: 16344560] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-218.
[7]	"Interaction of two actin-binding proteins, synaptopodin and alpha-actinin-4, with the tight junction protein MAGI-1." Patrie K.M., Drescher A.J., Welihinda A., Mundel P., Margolis B. J. Biol. Chem. 277:30183-30190(2002) [PubMed: 12042308] [Abstract] Cited for: INTERACTION WITH BAIAP1.
[8]	"CART: an Hrs/actinin-4/BERP/myosin V protein complex required for efficient receptor recycling." Yan Q., Sun W., Kujala P., Lotfi Y., Vida T.A., Bean A.J. Mol. Biol. Cell 16:2470-2482(2005) [PubMed: 15772161] [Abstract] Cited for: IDENTIFICATION IN THE CART COMPLEX.
[9]	"Immunoaffinity profiling of tyrosine phosphorylation in cancer cells." Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H., Zha X.-M., Polakiewicz R.D., Comb M.J. Nat. Biotechnol. 23:94-101(2005) [PubMed: 15592455] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-265, MASS SPECTROMETRY.
[10]	"Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer." Rikova K., Guo A., Zeng Q., Possemato A., Yu J., Haack H., Nardone J., Lee K., Reeves C., Li Y., Hu Y., Tan Z., Stokes M., Sullivan L., Mitchell J., Wetzel R., Macneill J., Ren J.M. , Yuan J., Bakalarski C.E., Villen J., Kornhauser J.M., Smith B., Li D., Zhou X., Gygi S.P., Gu T.-L., Polakiewicz R.D., Rush J., Comb M.J. Cell 131:1190-1203(2007) [PubMed: 18083107] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-265, MASS SPECTROMETRY. Tissue: Lung carcinoma.
[11]	"Molecular composition of IMP1 ribonucleoprotein granules." Joeson L., Vikesaa J., Krogh A., Nielsen L.K., Hansen T., Borup R., Johnsen A.H., Christiansen J., Nielsen F.C. Mol. Cell. Proteomics 6:798-811(2007) [PubMed: 17289661] [Abstract] Cited for: IDENTIFICATION IN A MRNP GRANULE COMPLEX, IDENTIFICATION BY MASS SPECTROMETRY, SUBCELLULAR LOCATION.
[12]	"Tryptic digestion of ubiquitin standards reveals an improved strategy for identifying ubiquitinated proteins by mass spectrometry." Denis N.J., Vasilescu J., Lambert J.-P., Smith J.C., Figeys D. Proteomics 7:868-874(2007) [PubMed: 17370265] [Abstract] Cited for: UBIQUITINATION [LARGE SCALE ANALYSIS] AT LYS-378, MASS SPECTROMETRY. Tissue: Mammary cancer.
[13]	"Lysine acetylation targets protein complexes and co-regulates major cellular functions." Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T., Olsen J.V., Mann M. Science 325:834-840(2009) [PubMed: 19608861] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-114; LYS-214; LYS-417; LYS-592 AND LYS-625, MASS SPECTROMETRY.
[14]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed: 21269460] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[15]	"Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis." Kaplan J.M., Kim S.H., North K.N., Rennke H., Correia L.A., Tong H.-Q., Mathis B.J., Rodriguez-Perez J.-C., Allen P.G., Beggs A.H., Pollak M.R. Nat. Genet. 24:251-256(2000) [PubMed: 10700177] [Abstract] Cited for: VARIANTS FSGS1 GLU-255; ILE-259 AND PRO-262. Tissue: Lymphocyte.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

D89980 mRNA. Translation: BAA24447.1. Different initiation.
U48734 mRNA. Translation: AAC17470.1. Frameshift.
BC005033 mRNA. Translation: AAH05033.1.
AL047603 mRNA. No translation available.
AU118403 mRNA. No translation available.

IPI

IPI00013808.

RefSeq

NP_004915.2. NM_004924.4.

UniGene

Hs.270291.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1WLX	NMR	-	A	519-645	[»]
1YDI	X-ray	1.80	B	734-757	[»]
2R0O	X-ray	2.20	A/B	47-271	[»]

ProteinModelPortal

O43707.

SMR

O43707. Positions 47-271, 286-911.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-33179N.

IntAct

O43707. 19 interactions.

MINT

MINT-4998602.

STRING

O43707.

PTM databases

PhosphoSite

O43707.

2D gel databases

REPRODUCTION-2DPAGE

O43707.

Proteomic databases

PeptideAtlas

O43707.

PRIDE

O43707.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000252699; ENSP00000252699; ENSG00000130402.

GeneID

81.

KEGG

hsa:81.

UCSC

uc002oja.1. human.

Organism-specific databases

CTD

81.

GeneCards

GC19P039138.

H-InvDB

HIX0015097.

HGNC

HGNC:166. ACTN4.

HPA

HPA001873.
HPA006035.

MIM

603278. phenotype.
604638. gene.

neXtProt

NX_O43707.

Orphanet

93213. Familial idiopathic steroid-resistant nephrotic syndrome with focal segmental hyalinosis.

PharmGKB

PA23.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG18779.

HOGENOM

HBG314462.

HOVERGEN

HBG050453.

InParanoid

O43707.

OMA

KPPRVEQ.

OrthoDB

EOG49P9XR.

PhylomeDB

O43707.

Enzyme and pathway databases

Reactome

REACT_111155. Cell-Cell communication.
REACT_604. Hemostasis.

Gene expression databases

ArrayExpress

O43707.

Bgee

O43707.

CleanEx

HS_ACTN4.

Genevestigator

O43707.

GermOnline

ENSG00000130402. Homo sapiens.

Family and domain databases

InterPro

IPR001589. Actinin_actin-bd_CS.
IPR001715. CH-domain.
IPR011992. EF-hand-like_dom.
IPR014837. EF-hand_Ca_insen.
IPR018247. EF_Hand_1_Ca_BS.
IPR018249. EF_HAND_2.
IPR002048. EF_hand_Ca-bd.
IPR018159. Spectrin/alpha-actinin.
IPR002017. Spectrin_repeat.
[Graphical view]

Gene3D

G3DSA:1.10.418.10. Calponin-homology. 2 hits.
G3DSA:1.10.238.10. EF-Hand_type. 2 hits.

KO

K05699.

Pfam

PF00307. CH. 2 hits.
PF08726. efhand_Ca_insen. 1 hit.
PF00435. Spectrin. 4 hits.
[Graphical view]

SMART

SM00033. CH. 2 hits.
SM00054. EFh. 2 hits.
SM00150. SPEC. 4 hits.
[Graphical view]

SUPFAM

SSF47576. Calponin-homology. 1 hit.

PROSITE

PS00019. ACTININ_1. 1 hit.
PS00020. ACTININ_2. 1 hit.
PS50021. CH. 2 hits.
PS00018. EF_HAND_1. 1 hit.
PS50222. EF_HAND_2. 2 hits.
[Graphical view]

ProtoNet

Search...

Other

NextBio

303.

PMAP-CutDB

O43707.

SOURCE

Search...

Entry information

Entry name

ACTN4_HUMAN

Accession

Primary (citable) accession number: O43707
Secondary accession number(s): O76048

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 21, 2001
Last sequence update:	February 21, 2001
Last modified:	January 25, 2012
This is version 143 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.