Alpha-actinin-4 - Homo sapiens (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)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

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

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Protein attributes

Sequence length	911 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

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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.
Subunit structure	Homodimer; antiparallel By similarity. Binds TRIM3 at the N-terminus By similarity. 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.
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.

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Ontologies

Keywords
Cellular component	Cytoplasm Nucleus
Disease	Disease mutation
Domain	Repeat
Ligand	Actin-binding Calcium
PTM	Phosphoprotein Ubl conjugation
Technical term	3D-structure
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	nucleus Ref.1 Inferred from direct assay. Source: UniProtKB 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 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...

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Binary interactions

With	Entry	#Exp.	IntAct	Notes
CTNNB1	P35222	1	EBI-351526,EBI-491549
TJP1	Q07157	2	EBI-351526,EBI-79553

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Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Molecule processing

Chain

1 – 911

911

Alpha-actinin-4

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

Cross-link

378

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

Natural variations

Natural variant

255

1

K → E in FSGS1.

Natural variant

259

1

T → I in FSGS1.

Natural variant

262

1

S → P in FSGS1.

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 and 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

.

911

Helix Strand Turn

Details...

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Sequences

Sequence

Length

Mass (Da)

Tools

O43707-1 [UniParc].

Last modified February 21, 2001. Version 2.
Checksum: 461580C3F22937D1
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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

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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 German cDNA consortium Submitted (FEB-2000) to the EMBL/GenBank/DDBJ databases 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]	"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.
[9]	"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. Comb M.J. Cell 131:1190-1203(2007) [PubMed: 18083107] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-265, MASS SPECTROMETRY.
[10]	"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.
[11]	"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.

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Web resources

GeneReviews

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Cross-references

Sequence databases

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.

RefSeq

NP_004915.2.

UniGene

Hs.270291

3D structure databases

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	44-271	[»]

SMR

O43707. Positions 44-911.

ModBase

Search...

Protein-protein interaction databases

IntAct

O43707.

PTM databases

PhosphoSite

O43707.

2-D gel databases

REPRODUCTION-2DPAGE

O43707.

Proteomic databases

PeptideAtlas

O43707.

Genome annotation databases

Ensembl

ENSG00000130402. Homo sapiens. [Contig view]

GeneID

81.

KEGG

hsa:81.

Organism-specific databases

H-InvDB

HIX0015097.

HGNC

HGNC:166. ACTN4.

Names and origin

Protein attributes

General annotation (Comments)

Ontologies

Keywords

Gene Ontology (GO)

Binary interactions

With

Entry

#Exp.

IntAct

Notes

Sequence annotation (Features)

Molecule processing

Regions

Amino acid modifications

Natural variations

Experimental info

Secondary structure

Sequences

References

Web resources

Cross-references

Sequence databases

3D structure databases

Protein-protein interaction databases

PTM databases

2-D gel databases

Proteomic databases

Genome annotation databases

Organism-specific databases