Q96M96 (FGD4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
FYVE, RhoGEF and PH domain-containing protein 4

Alternative name(s):
Actin filament-binding protein frabin
FGD1-related F-actin-binding protein
Zinc finger FYVE domain-containing protein 6

Gene names

Name:	FGD4
Synonyms:	FRABP, ZFYVE6

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	766 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Activates CDC42, a member of the Ras-like family of Rho- and Rac proteins, by exchanging bound GDP for free GTP. Plays a role in regulating the actin cytoskeleton and cell shape. Activates MAPK8 By similarity. Ref.4
Subunit structure	Homooligomer By similarity.
Subcellular location	Cytoplasm › cytoskeleton By similarity. Cell projection › filopodium By similarity. Note: Concentrated in filopodia and poorly detected at lamellipodia. Binds along the sides of actin fibers By similarity.
Tissue specificity	Expressed in different tissues, including brain, cerebellum, peripheral nerve, skeletal muscle, heart, uterus, placenta and testis. Ref.5
Domain	The part of the protein spanning the actin filament-binding domain together with the DH domain and the first PH domain is necessary and sufficient for microspike formation. Activation of MAPK8 requires the presence of all domains with the exception of the actin filament-binding domain By similarity.
Involvement in disease	Charcot-Marie-Tooth disease 4H (CMT4H) [MIM:609311]: A recessive demyelinating form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Demyelinating neuropathies are characterized by severely reduced nerve conduction velocities (less than 38 m/sec), segmental demyelination and remyelination with onion bulb formations on nerve biopsy, slowly progressive distal muscle atrophy and weakness, absent deep tendon reflexes, and hollow feet. By convention autosomal recessive forms of demyelinating Charcot-Marie-Tooth disease are designated CMT4. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.5 Ref.6
Sequence similarities	Contains 1 DH (DBL-homology) domain. Contains 1 FYVE-type zinc finger. Contains 2 PH domains.

Ontologies

Keywords
Cellular component	Cell projection Cytoplasm Cytoskeleton
Coding sequence diversity	Alternative splicing
Disease	Charcot-Marie-Tooth disease Disease mutation Neuropathy
Domain	Repeat Zinc-finger
Ligand	Actin-binding Metal-binding Zinc
Molecular function	Guanine-nucleotide releasing factor
PTM	Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	actin cytoskeleton organization Inferred from sequence or structural similarity. Source: UniProtKB apoptotic process Traceable author statement. Source: Reactome filopodium assembly Inferred from sequence or structural similarity. Source: UniProtKB lamellipodium assembly Inferred from electronic annotation. Source: Compara microspike assembly Inferred from electronic annotation. Source: Compara nerve growth factor receptor signaling pathway Traceable author statement. Source: Reactome regulation of Cdc42 GTPase activity Inferred from sequence or structural similarity. Source: UniProtKB regulation of cell shape Inferred from sequence or structural similarity. Source: UniProtKB small GTPase mediated signal transduction Traceable author statement. Source: Reactome
Cellular_component	Golgi apparatus Inferred from sequence or structural similarity. Source: UniProtKB actin cytoskeleton Inferred from direct assay. Source: HPA cytosol Traceable author statement. Source: Reactome filopodium Inferred from electronic annotation. Source: UniProtKB-SubCell lamellipodium Inferred from sequence or structural similarity. Source: UniProtKB ruffle Inferred from sequence or structural similarity. Source: UniProtKB
Molecular_function	Rho guanyl-nucleotide exchange factor activity Inferred from electronic annotation. Source: InterPro guanyl-nucleotide exchange factor activity Inferred from sequence or structural similarity. Source: UniProtKB metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW phospholipid binding Inferred from electronic annotation. Source: InterPro small GTPase binding Inferred from sequence or structural similarity. Source: UniProtKB
Complete GO annotation...

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]

Note: Additional isoforms seem to exist.

Isoform 1 (identifier: Q96M96-1)

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: Q96M96-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-248: Missing.
     515-766: ALQETIDAFH...HPEPKKKSEC → RRGFAMLPRLISNS

Note: No experimental confirmation available.

Isoform 3 (identifier: Q96M96-3)

The sequence of this isoform differs from the canonical sequence as follows:
     1-30: MEEIKPASASCVSKEKPSKVSDLISRFEGG → MFSCFLCILSF
     201-207: ETNEQKL → VEHETSS
     208-766: Missing.

Note: No experimental confirmation available.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 766	766	FYVE, RhoGEF and PH domain-containing protein 4		PRO_0000080947
Regions
	Domain	206 – 393	188	DH
	Domain	422 – 521	100	PH 1
	Domain	643 – 740	98	PH 2
	Zinc finger	559 – 619	61	FYVE-type
	Region	1 – 150	150	Actin filament-binding By similarity
Amino acid modifications
	Modified residue	702	1	Phosphoserine By similarity
Natural variations
	Alternative sequence	1 – 248	248	Missing in isoform 2.		VSP_013078
	Alternative sequence	1 – 30	30	MEEIK…RFEGG → MFSCFLCILSF in isoform 3.		VSP_013079
	Alternative sequence	201 – 207	7	ETNEQKL → VEHETSS in isoform 3.		VSP_013080
	Alternative sequence	208 – 766	559	Missing in isoform 3.		VSP_013081
	Alternative sequence	515 – 766	252	ALQET…KKSEC → RRGFAMLPRLISNS in isoform 2.		VSP_013082
	Natural variant	298	1	M → R in fibroblasts from a CMT4H patient; absent from patient's peripheral nerve where splicing defects and aberrant transcripts are detected. Ref.5 Ref.6		VAR_034957
	Natural variant	298	1	M → T in CMT4H. Ref.5		VAR_044321
Experimental info
	Sequence conflict	79	1	T → A in BAB71413. Ref.2
	Sequence conflict	303	1	V → A in AAQ72372. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified October 17, 2006. Version 2. Checksum: B919A7C1D164B05D	FASTA	766	86,626
	10 20 30 40 50 60 MEEIKPASAS CVSKEKPSKV SDLISRFEGG SSLSNYSDLK KESAVNLNAP RTPGRHGLTT 70 80 90 100 110 120 TPQQKLLSQH LPQRQGNDTD KTQGAQTCVA NGVMAAQNQM ECEEEKAATL SSDTSIQASE 130 140 150 160 170 180 PLLDTHIVNG ERDETATAPA SPTTDSCDGN ASDSSYRTPG IGPVLPLEER GAETETKVQE 190 200 210 220 230 240 RENGESPLEL EQLDQHHEMK ETNEQKLHKI ANELLLTERA YVNRLDLLDQ VFYCKLLEEA 250 260 270 280 290 300 NRGSFPAEMV NKIFSNISSI NAFHSKFLLP ELEKRMQEWE TTPRIGDILQ KLAPFLKMYG 310 320 330 340 350 360 EYVKGFDNAM ELVKNMTERI PQFKSVVEEI QKQKICGSLT LQHHMLEPVQ RIPRYEMLLK 370 380 390 400 410 420 DYLRKLPPDS LDWNDAKKSL EIISTAASHS NSAIRKMENL KKLLEIYEML GEEEDIVNPS 430 440 450 460 470 480 NELIKEGQIL KLAARNTSAQ ERYLFLFNNM LLYCVPKFSL VGSKFTVRTR VGIDGMKIVE 490 500 510 520 530 540 TQNEEYPHTF QVSGKERTLE LQASSAQDKE EWIKALQETI DAFHQRHETF RNAIAKDNDI 550 560 570 580 590 600 HSEVSTAELG KRAPRWIRDN EVTMCMKCKE PFNALTRRRH HCRACGYVVC WKCSDYKAQL 610 620 630 640 650 660 EYDGGKLSKV CKDCYQIISG FTDSEEKKRK GILEIESAEV SGNSVVCSFL QYMEKSKPWQ 670 680 690 700 710 720 KAWCVIPKQD PLVLYMYGAP QDVRAQATIP LLGYVVDEMP RSADLPHSFK LTQSKSVHSF 730 740 750 760 AADSEELKQK WLKVILLAVT GETPGGPNEH PATLDDHPEP KKKSEC
	Isoform 2 [UniParc]. Checksum: 1F353FCAB39FA086	FASTA	280	32,521
	10 20 30 40 50 60 MVNKIFSNIS SINAFHSKFL LPELEKRMQE WETTPRIGDI LQKLAPFLKM YGEYVKGFDN 70 80 90 100 110 120 AMELVKNMTE RIPQFKSVVE EIQKQKICGS LTLQHHMLEP VQRIPRYEML LKDYLRKLPP 130 140 150 160 170 180 DSLDWNDAKK SLEIISTAAS HSNSAIRKME NLKKLLEIYE MLGEEEDIVN PSNELIKEGQ 190 200 210 220 230 240 ILKLAARNTS AQERYLFLFN NMLLYCVPKF SLVGSKFTVR TRVGIDGMKI VETQNEEYPH 250 260 270 280 TFQVSGKERT LELQASSAQD KEEWIKRRGF AMLPRLISNS
	Isoform 3 [UniParc]. Checksum: EDFB9CE574C0495D	FASTA	188	20,388
	10 20 30 40 50 60 MFSCFLCILS FSSLSNYSDL KKESAVNLNA PRTPGRHGLT TTPQQKLLSQ HLPQRQGNDT 70 80 90 100 110 120 DKTQGAQTCV ANGVMAAQNQ MECEEEKAAT LSSDTSIQAS EPLLDTHIVN GERDETATAP 130 140 150 160 170 180 ASPTTDSCDG NASDSSYRTP GIGPVLPLEE RGAETETKVQ ERENGESPLE LEQLDQHHEM KVEHETSS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Cloning a new transcript of actin-filament binding protein frabin in testis." Lu L., Huang X.Y., Xu M., Yin L.L., Li J.M., Zhou Z.M., Sha J.H. Submitted (AUG-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2). Tissue: Testis.
[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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). Tissue: Testis.
[3]	"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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3). Tissue: Testis.
[4]	"Phosphatidylinositol 3-kinase and frabin mediate Cryptosporidium parvum cellular invasion via activation of Cdc42." Chen X.M., Splinter P.L., Tietz P.S., Huang B.Q., Billadeau D.D., LaRusso N.F. J. Biol. Chem. 279:31671-31678(2004) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[5]	"Mutations in FGD4 encoding the Rho GDP/GTP exchange factor FRABIN cause autosomal recessive Charcot-Marie-Tooth type 4H." Delague V., Jacquier A., Hamadouche T., Poitelon Y., Baudot C., Boccaccio I., Chouery E., Chaouch M., Kassouri N., Jabbour R., Grid D., Megarbane A., Haase G., Levy N. Am. J. Hum. Genet. 81:1-16(2007) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT CMT4H THR-298, VARIANT ARG-298, TISSUE SPECIFICITY, ALTERNATIVE SPLICING.
[6]	"Peripheral nerve demyelination caused by a mutant Rho GTPase guanine nucleotide exchange factor, frabin/FGD4." Stendel C., Roos A., Deconinck T., Pereira J., Castagner F., Niemann A., Kirschner J., Korinthenberg R., Ketelsen U.-P., Battaloglu E., Parman Y., Nicholson G., Ouvrier R., Seeger J., De Jonghe P., Weis J., Kruettgen A., Rudnik-Schoeneborn S. , Bergmann C., Suter U., Zerres K., Timmerman V., Relvas J.B., Senderek J. Am. J. Hum. Genet. 81:158-164(2007) [PubMed] [Europe PMC] [Abstract] Cited for: INVOLVEMENT IN CMT4H, VARIANT ARG-298.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases
EMBL GenBank DDBJ	AY367054 mRNA. Translation: AAQ72372.1. AK057294 mRNA. Translation: BAB71413.1. AL713762 mRNA. Translation: CAD28532.1.
IPI	IPI00065435. IPI00429579. IPI00940940.
RefSeq	NP_640334.2. NM_139241.2.
UniGene	Hs.117835.
3D structure databases
ProteinModelPortal	Q96M96.
ModBase	Search...
Protein-protein interaction databases
STRING	9606.ENSP00000394487.
PTM databases
PhosphoSite	Q96M96.
Polymorphism databases
DMDM	116241363.
Proteomic databases
PaxDb	Q96M96.
PRIDE	Q96M96.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000381025; ENSP00000370413; ENSG00000139132. ENST00000427716; ENSP00000394487; ENSG00000139132.
GeneID	121512.
KEGG	hsa:121512.
UCSC	uc001rkz.3. human.
Organism-specific databases
CTD	121512.
GeneCards	GC12P032546.
HGNC	HGNC:19125. FGD4.
HPA	HPA039235.
MIM	609311. phenotype. 611104. gene.
neXtProt	NX_Q96M96.
Orphanet	99954. Charcot-Marie-Tooth disease type 4H.
PharmGKB	PA134907925.
GenAtlas	Search...
Phylogenomic databases
eggNOG	COG5422.
HOVERGEN	HBG007506.
InParanoid	Q96M96.
KO	K05723.
OrthoDB	EOG418BMQ.
PhylomeDB	Q96M96.
Enzyme and pathway databases
Reactome	REACT_111102. Signal Transduction.
Gene expression databases
ArrayExpress	Q96M96.
Bgee	Q96M96.
CleanEx	HS_FGD4.
Genevestigator	Q96M96.
GermOnline	ENSG00000139132. Homo sapiens.
Family and domain databases
Gene3D	1.20.900.10. 1 hit. 2.30.29.30. 2 hits. 3.30.40.10. 1 hit.
InterPro	IPR000219. DH-domain. IPR011993. PH_like_dom. IPR001849. Pleckstrin_homology. IPR000306. Znf_FYVE. IPR017455. Znf_FYVE-rel. IPR011011. Znf_FYVE_PHD. IPR013083. Znf_RING/FYVE/PHD. [Graphical view]
Pfam	PF01363. FYVE. 1 hit. PF00169. PH. 2 hits. PF00621. RhoGEF. 1 hit. [Graphical view]
SMART	SM00064. FYVE. 1 hit. SM00233. PH. 2 hits. SM00325. RhoGEF. 1 hit. [Graphical view]
SUPFAM	SSF48065. DH-domain. 1 hit. SSF57903. FYVE_PHD_ZnF. 1 hit.
PROSITE	PS50010. DH_2. 1 hit. PS50003. PH_DOMAIN. 2 hits. PS50178. ZF_FYVE. 1 hit. [Graphical view]
ProtoNet	Search...
Other
ChiTaRS	FGD4. human.
GenomeRNAi	121512.
NextBio	80759.
SOURCE	Search...

Entry information

Entry name

FGD4_HUMAN

Accession

Primary (citable) accession number: Q96M96
Secondary accession number(s): Q6ULS2, Q8TCP6

Entry history

Integrated into UniProtKB/Swiss-Prot:	March 15, 2005
Last sequence update:	October 17, 2006
Last modified:	May 1, 2013
This is version 105 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.