Reviewed, UniProtKB/Swiss-Prot O43707 (ACTN4_HUMAN)

Names and origin

Protein names

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

Gene names

Name:

ACTN4

Organism

Homo sapiens (Human) [Complete proteome]

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.
Sequence processing	The displayed sequence is not processed.
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. Component of the CART complex, at least composed of ACTN4, HGS/HRS, MYO5B and TRIM3. Interacts with BAIAP1 and PDLIM2.
Subcellular location	Nucleus. Cytoplasm. Note: 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).
Tissue specificity	Widely expressed.
Involvement in disease	Cytoplasmic localization of ACTN4 may be associated with cancer metastases due to enhanced cell motility. Defects in ACTN4 are the cause of focal segmental glomerulosclerosis 1 (FSGS1) [MIM:603278]. FSGS1 is a common renal lesion characterized by increased urinary protein excretion (proteinuria) and decreasing kidney function (nephrotic syndrome). Renal insufficiency often progresses to end-stage renal disease (ESRD) (also known as end-stage renal failure), a highly morbid state requiring either dialysis therapy or kidney transplantation. FSGS1 is defined by the presence of segmental sclerosis in glomeruli, and is seen in all ethnic groups, although it is particularly common in individuals of African descent. FSGS1 occurs as an isolated primary condition or secondary to disorders as HIV infection, obesity, hypertension and diabetes. FSGS1 may also be inherited as a Mendelian trait. Ref.13
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 several positions. The sequence AAC17470.1 differs from that shown. Reason: Miscellaneous discrepancy. Sequencing errors. Compared to other mammalian sequences.

Ontologies

Keywords
Biological process	Protein transport Transport
Cellular component	Cytoplasm Nucleus
Disease	Disease mutation
Domain	Repeat
Ligand	Actin-binding Calcium
PTM	Isopeptide bond Phosphoprotein Ubl conjugation
Technical term	3D-structure Complete proteome
Gene Ontology (GO)
Biological process	positive regulation of cell motion Ref.1 Inferred from direct assay. Source: UniProtKB positive regulation of sodium:hydrogen antiporter activity Non-traceable author statement. Source: UniProtKB regulation of apoptosis Non-traceable author statement. Source: UniProtKB
Cellular component	nucleolus Inferred from direct assay. Source: HPA perinuclear region of cytoplasm Inferred from direct assay. Source: UniProtKB protein complex Inferred from direct assay. Source: UniProtKB pseudopodium Traceable author statement. Source: UniProtKB
Molecular function	actin filament binding Inferred from direct assay. Source: UniProtKB calcium ion binding Inferred from electronic annotation. Source: UniProtKB-KW 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	1	EBI-351526,EBI-491549
TJP1	Q07157	2	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

265

1

Phosphotyrosine Ref.9 Ref.10

Cross-link

378

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) Ref.11

Natural variations

Natural variant

255

1

K → E in FSGS1. Ref.13

VAR_010378

Natural variant

259

1

T → I in FSGS1. Ref.13

VAR_010379

Natural variant

262

1

S → P in FSGS1. Ref.13

VAR_010380

Experimental info

Sequence conflict

60

1

C → S in AAC17470. Ref.3

Sequence conflict

124

1

V → I 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 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

859

1

Missing Ref.3

Sequence conflict

891 – 893

3

AVP → GVR in AAC17470. Ref.3

Secondary structure

1

.

.

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.

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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)
	O43707-1 [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., Blocker H., Heubner D., Hoerlein A., Michel G., Wedler H., Kohrer K., Ottenwalder 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]	Isogai T., Otsuki T., Sugiyama T. Submitted (OCT-2000) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [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.
[11]	"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.
[12]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[13]	"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

EMBLGenBankDDBJ

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

IPI

IPI00013808.

RefSeq

NP_004915.2.

UniGene

Hs.270291

3D structure databases

PDBPDBe

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	[»]

SMR

O43707. Positions 44-911.

ModBase

Search...

Protein-protein interaction databases

IntAct

O43707. 15 interactions.

PTM databases

PhosphoSite

O43707.

2-D gel databases

REPRODUCTION-2DPAGE

O43707.

Proteomic databases

PeptideAtlas

O43707.

PRIDE

O43707.

Genome annotation databases

Ensembl

ENSG00000130402. Homo sapiens. [Contig view]

GeneID

81.

KEGG

hsa:81.

UCSC

uc002oja.1. human.

Organism-specific databases

GeneCards

GC19P043830.

H-InvDB

HIX0015097.

HGNC

HGNC:166. ACTN4.

HPA

HPA001873.
HPA006035.

MIM

603278. phenotype.
604638. gene.

Orphanet

656. Nephrotic syndrome, idiopathic, steroid-resistant, familial.

PharmGKB

PA23.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

O43707.

HOVERGEN

O43707.

OMA

O43707. DAEFNRI.

Enzyme and pathway databases

Reactome

REACT_604. Hemostasis.

Gene expression databases

ArrayExpress

O43707.

Bgee

O43707.

CleanEx

HS_ACTN4.

GermOnline

ENSG00000130402. Homo sapiens.

Family and domain databases

InterPro

IPR001589. Actinin_actin-bd_CS.
IPR001715. Calponin_act_bd.
IPR014837. EF-hand_Ca_insen.
IPR011992. EF-Hand_type.
IPR018248. EF_hand.
IPR018247. EF_HAND_1.
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.

Pfam

PF00307. CH. 2 hits.
PF00036. efhand. 2 hits.
PF08726. efhand_Ca_insen. 1 hit.
PF00435. Spectrin. 4 hits.
[Graphical view]

ProDom

PD000012. EF-hand. 1 hit.
[Graphical view] [Entries sharing at least one domain]

SMART

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

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 Resources

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:	July 7, 2009
This is version 115 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)