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The FYVE domain has been named after the first letter of the first four proteins in which it was found (Fab1, YOTB/ZK632.12, Vac1, and EEA1). It is a cysteine-rich domain of about 70 amino acids that coordinates two Zn2+ ions. The FYVE domain is found in several eukaryotic non-nuclear proteins involved in distinct cellular functions, including vesicle transport, signal transduction and cytoskeletal regulation. FYVE domains are generally found in one copy but two copies can also be found. Positions of FYVE domains in different proteins vary from the extreme N-terminus to the extreme C-terminus. FYVE domains are found associated with other domains such as IQ (see <PDOC50096>), PH (see <PDOC50003>), VHS, RCC, SH2 (see <PDOC50001>), RING finger (see <PDOC00449>) or C2H2 zinc finger (see <PDOC00028>) [1,2,3]. The function of the FYVE domain is to target signal-transducing proteins to cell membranes through binding to the membrane lipid phosphatidylinositol-3-phosphate (PtdIns(3)P) with high specificity [4,5].

The FYVE domain has eight conserved cysteines, which coordinate the two Zn2+ ions in a 'cross-braced' topology: the first Zn2+ ion is coordinated by the first and third pairs of cysteines, and the second ion is coordinated by the second and fourth pairs. In addition, the FYVE domain contains several other conserved residues, most prominently a basic R-[RK]-H-H-C-R-x-C-G motif surrounding the third and fourth cysteine residues. Several hydrophobic amino acid positions are also conserved among the FYVE fingers, as is an isolated arginine residue towards the C-terminus [2,6]. Resolution of the crystal and solution structures of the FYVE domain has shown that it consists of two double-stranded antiparallel β-sheets, which are stabilized by the two zinc ions and a C-terminal α-helix. The conserved R-[RK]-H-H-C-R-x-C-G motif and the conserved arginine residue form a basic pocket involved in the inositol head group binding [6,7].

The FYVE-related domain is found in several proteins involved in regulated secretion, such as Rabphilin-3A and Rim. Although the structure of the FYVE-related domain is closely related to the one of the genuine FYVE domain, the FYVE-related domain lacks several of the conserved feature of the FYVE domain, like the basic R-[RK]-H-H-C-R-x-C-G motif, and it does not bind to PtdIns(3)P [2,4,6].

Some proteins known to contain a FYVE or a FYVE-related domain are listed below:

• Animal Hrs, an hepatocyte growth factor-regulated tyrosine kinase substrate. Hrs is localised to early endosomes in a manner that requires phosphoinositide 3-kinase (PI 3-kinase) activity.
• Animal Smad anchor for receptor activation (SARA), an important mediator of transforming growth factor β (TGF-β) signalling. It is responsible for the recruitment of Smad2 and Smad3 to the TGF-β receptor upon receptor stimulation.
• Mammalian Fgd1, a protein implicated in cytoskeletal regulation. It acts as a guanine nucleotide exchange factor for Cdc42, a Rho-family GTPase that controls the submembraneous actin cytoskeleton. In human, mutations in the gene coding for the Fgd1 protein are associated with faciogenital dysplasia, an X-linked autosomal disease primarily associated with skeletal, facial and genital anomalies.
• Mammalian early endosome antigen 1 (EEA1), which fuses endosome and relies on its FYVE domain for specific localization to PtdIns(3)P-enriched membranes and for recruiting regulatory Rab5 and syntaxin proteins.
• Human Rabenosyn-5, a rab5 effector that is localized to early endosomes and required for endosome fusion.
• Caenorhabditis elegans hypothetical protein ZK632.12.
• Yeast VAC1 protein. It is required for vacuole segregation and vacuole protein sorting. Possibly part of a complex which tethers the vacuole membrane to microtubules, either directly or via kinesin or dynein-like motor proteins. Probably functions in several interorganelle traffic pathways.
• Yeast vacuolar protein sorting-associated protein VPS27. It is required for membrane traffic to the vacuole.
• Yeast FAB1 protein, a PI 5-kinase that converts PtdIns(3)-P into PtdIns(3,5)P2. It is implicated in the formation of multivesicular endosome.
• Animal rabphilin-3A, an effector of the Rab3A GTPase. Activated Rab3A reversibly recruits rabphilin-3A to synaptic vesicles.
• Mammalian proteins of the Rim family. They are effectors of the Rab3A GTPase. Rim proteins have sequence similarity to rabphilin-3A but localize to the active zone of the presynaptic plasma membrane instead of to synaptic vesicles.

The profile we developed covers the entire FYVE domain.

December 2001 / First entry.

PROSITE method (with tools and information) covered by this documentation:

ZF_FYVE, PS50178; Zinc finger FYVE/FYVE-related type profile  (MATRIX)

Sequences known to belong to this class detected by the profile: ALL Other sequence(s) detected in Swiss-Prot: NONE

• Domain architecture view of Swiss-Prot proteins matching PS50178 • Retrieve an alignment of Swiss-Prot true positive hits:   Clustal format, color, condensed view  / Clustal format, color  / Clustal format, plain text  / Fasta format • Retrieve the sequence logo from the alignment • Taxonomic tree view of all Swiss-Prot/TrEMBL entries matching PS50178 • Retrieve a list of all Swiss-Prot/TrEMBL entries matching PS50178 • Scan Swiss-Prot/TrEMBL entries against PS50178 • view ligand binding statistics

Matching PDB structures: 1DVP 1HYI 1HYJ 1JOC ... [ALL]

1	Authors	Stenmark H., Aasland R., Toh B.-H., D'Arrigo A.
	Title	Endosomal localization of the autoantigen EEA1 is mediated by a zinc-binding FYVE finger.
	Source	J. Biol. Chem. 271:24048-24054(1996).
	PubMed ID	8798641

2	Authors	Stenmark H., Aasland R.
	Title	FYVE-finger proteins--effectors of an inositol lipid.
	Source	J. Cell Sci. 112:4175-4183(1999).
	PubMed ID	10564636

3	Authors	Gillooly D.J., Simonsen A., Stenmark H.
	Title	Cellular functions of phosphatidylinositol 3-phosphate and FYVE domain proteins.
	Source	Biochem. J. 355:249-258(2001).
	PubMed ID	11284710

4	Authors	Gaullier J.-M., Simonsen A., D'Arrigo A., Bremnes B., Stenmark H., Aasland R.
	Title	FYVE fingers bind PtdIns(3)P.
	Source	Nature 394:432-433(1998).
	PubMed ID	9697764
	DOI	10.1038/28767

5	Authors	Patki V., Lawe D.C., Corvera S., Virbasius J.V., Chawla A.
	Title	A functional PtdIns(3)P-binding motif.
	Source	Nature 394:433-434(1998).
	PubMed ID	9697765
	DOI	10.1038/28771

6	Authors	Misra S., Hurley J.H.
	Title	Crystal structure of a phosphatidylinositol 3-phosphate-specific membrane-targeting motif, the FYVE domain of Vps27p.
	Source	Cell 97:657-666(1999).
	PubMed ID	10367894

7	Authors	Kutateladze T., Overduin M.
	Title	Structural mechanism of endosome docking by the FYVE domain.
	Source	Science 291:1793-1796(2001).
	PubMed ID	11230696
	DOI	10.1126/science.291.5509.1793;

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