ADP ribosylation factor
Encyclopedia
ADP Ribosylation Factors (ARFs) are members of the ARF family of GTP-binding proteins of the Ras superfamily
. ARF family proteins are ubiquitous in eukaryotic cells, and six highly conserved members of the family have been identified in mammalian cells. Although ARFs are soluble, they generally associate with membranes because of N-terminus myristoylation
. They function as regulators of vesicular
traffic and actin
remodelling.
The small ADP ribosylation factor (Arf) GTP-binding proteins are major regulators of vesicle biogenesis in intracellular traffic. They are the founding members of a growing family that includes Arl (Arf-like), Arp (Arf-related proteins) and the remotely related Sar (Secretion-associated and Ras-related) proteins. Arf proteins cycle between inactive GDP-bound and active GTP-bound forms that bind selectively to effectors. The classical structural GDP/GTP switch is characterised by conformational changes at the so-called switch 1 and switch 2 regions, which bind tightly to the gamma-phosphate of GTP but poorly or not at all to the GDP nucleotide. Structural studies of Arf1 and Arf6 have revealed that although these proteins feature the switch 1 and 2 conformational changes, they depart from other small GTP-binding proteins in that they use an additional, unique switch to propagate structural information from one side of the protein to the other.
The GDP/GTP structural cycles of human Arf1 and Arf6 feature a unique conformational change that affects the beta2beta3 strands connecting switch 1 and switch 2 (interswitch) and also the amphipathic helical N-terminus. In GDP-bound Arf1 and Arf6,
the interswitch is retracted and forms a pocket to which the N-terminal helix binds, the latter serving as a molecular hasp
to maintain the inactive conformation. In the GTP-bound form of these proteins, the interswitch undergoes a two-residue register shift that pulls switch 1 and switch 2 up, restoring an active conformation that can bind GTP. In this conformation, the interswitch projects out of the protein and extrudes the N-terminal hasp by occluding its binding pocket.
(GTP) and guanosine diphosphate
(GDP). The shape of the ARF molecule is dependent upon which form it is bound to, allowing it to serve in a regulatory capacity. ARF requires assistance from other proteins in order to switch between binding to GTP and GDP. GTPase activating protein
s (GAPs) force ARF to hydrolyze
bound GTP to GDP, and Guanine nucleotide exchange factor
s force ARF to adopt a new GTP molecule in place of a bound GDP.
) and various phospholipids. The inactive form is only know to bind to a class of transmembrane proteins.
Different types of ARF bind specifically different kinds of effector proteins.
There are currently 6 known mammalian ARF proteins, which are divided into three classes of ARFs:
in their N-terminal region, which contributes to their membrane association.
; ARF3
; ARF4
; ARF5
; ARF6
; ARFRP1
; ARL1
; ARL10;
ARL11
; ARL13A; ARL13B
; ARL14; ARL15; ARL16; ARL17; ARL2
;
ARL2L1; ARL3
; ARL4A
; ARL4C; ARL4D
; ARL5; ARL5A; ARL5B;
ARL6
; ARL7; ARL8A
; ARL8B
; ARL9; MGC57346; SAR1A; SAR1B
;
SAR1P3; SARA1; TRIM23
;
Ras superfamily
The Ras superfamily is a protein superfamily of small GTPases, which are all related, to a degree, to the Ras protein subfamily .There are more than a hundred proteins in the Ras superfamily...
. ARF family proteins are ubiquitous in eukaryotic cells, and six highly conserved members of the family have been identified in mammalian cells. Although ARFs are soluble, they generally associate with membranes because of N-terminus myristoylation
Myristoylation
Myristoylation is an irreversible, co-translational protein modification found in animals, plants, fungi, protozoans and viruses. In this protein modification, a myristoyl group is covalently attached via an amide bond to the alpha-amino group of an N-terminal amino acid of a nascent polypeptide...
. They function as regulators of vesicular
Vesicle (biology)
A vesicle is a bubble of liquid within another liquid, a supramolecular assembly made up of many different molecules. More technically, a vesicle is a small membrane-enclosed sack that can store or transport substances. Vesicles can form naturally because of the properties of lipid membranes , or...
traffic and actin
Actin
Actin is a globular, roughly 42-kDa moonlighting protein found in all eukaryotic cells where it may be present at concentrations of over 100 μM. It is also one of the most highly-conserved proteins, differing by no more than 20% in species as diverse as algae and humans...
remodelling.
The small ADP ribosylation factor (Arf) GTP-binding proteins are major regulators of vesicle biogenesis in intracellular traffic. They are the founding members of a growing family that includes Arl (Arf-like), Arp (Arf-related proteins) and the remotely related Sar (Secretion-associated and Ras-related) proteins. Arf proteins cycle between inactive GDP-bound and active GTP-bound forms that bind selectively to effectors. The classical structural GDP/GTP switch is characterised by conformational changes at the so-called switch 1 and switch 2 regions, which bind tightly to the gamma-phosphate of GTP but poorly or not at all to the GDP nucleotide. Structural studies of Arf1 and Arf6 have revealed that although these proteins feature the switch 1 and 2 conformational changes, they depart from other small GTP-binding proteins in that they use an additional, unique switch to propagate structural information from one side of the protein to the other.
The GDP/GTP structural cycles of human Arf1 and Arf6 feature a unique conformational change that affects the beta2beta3 strands connecting switch 1 and switch 2 (interswitch) and also the amphipathic helical N-terminus. In GDP-bound Arf1 and Arf6,
the interswitch is retracted and forms a pocket to which the N-terminal helix binds, the latter serving as a molecular hasp
to maintain the inactive conformation. In the GTP-bound form of these proteins, the interswitch undergoes a two-residue register shift that pulls switch 1 and switch 2 up, restoring an active conformation that can bind GTP. In this conformation, the interswitch projects out of the protein and extrudes the N-terminal hasp by occluding its binding pocket.
Regulatory proteins
ARFs regularly associate with two types of protein, those involved in catalyzing GTP/GDP exchange, and those that serve other functions.GTP/GDP exchange proteins
ARF binds to two forms of the guanosine nucleotide, guanosine triphosphateGuanosine triphosphate
Guanosine-5'-triphosphate is a purine nucleoside triphosphate. It can act as a substrate for the synthesis of RNA during the transcription process...
(GTP) and guanosine diphosphate
Guanosine diphosphate
Guanosine diphosphate, abbreviated GDP, is a nucleoside diphosphate. It is an ester of pyrophosphoric acid with the nucleoside guanosine. GDP consists of the pyrophosphate group, the pentose sugar ribose, and the nucleobase guanine....
(GDP). The shape of the ARF molecule is dependent upon which form it is bound to, allowing it to serve in a regulatory capacity. ARF requires assistance from other proteins in order to switch between binding to GTP and GDP. GTPase activating protein
GTPase activating protein
GTPase-Activating Proteins, or GAPs, or GTPase-Accelerating Proteins are a family of regulatory proteins whose members can bind to activated G proteins and stimulate their GTPase activity, with the result of terminating the signaling event...
s (GAPs) force ARF to hydrolyze
Hydrolysis
Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...
bound GTP to GDP, and Guanine nucleotide exchange factor
Guanine nucleotide exchange factor
Guanine nucleotide exchange factors activate monomeric GTPases by stimulating the release of guanosine diphosphate to allow binding of guanosine triphosphate . A variety of unrelated structural domains have been shown to exhibit guanine nucleotide exchange activity...
s force ARF to adopt a new GTP molecule in place of a bound GDP.
Other proteins
Other proteins interact with ARF, depending upon whether it is bound to GTP or GDP. The active form, ARF*GTP, binds to vesicle coat proteins and adaptors, including coat protein I (COPICOPI
COPI is a protein complex that coats vesicles transporting proteins from the cis end of the Golgi complex back to the rough endoplasmic reticulum , where they were originally synthesized and between golgi compartments. This type of transport is termed as retrograde transport...
) and various phospholipids. The inactive form is only know to bind to a class of transmembrane proteins.
Different types of ARF bind specifically different kinds of effector proteins.
Phylogeny
- class 1: , ,
- class 2: ,
- class 3: . (See also ARF6Arf6ADP-ribosylation factor 6 is a member of the ADP ribosylation factor family of GTP-binding proteins. ARF6 has a variety of cellular functions that are frequently involved in trafficking of biological membranes and transmembrane protein cargo...
)
Structure
ARFs are small proteins of approximately 20 kD in size. They contain two switch regions, which change relative positions between cycles of GDP/GTP-binding. ARFs are frequently myristoylatedMyristoylation
Myristoylation is an irreversible, co-translational protein modification found in animals, plants, fungi, protozoans and viruses. In this protein modification, a myristoyl group is covalently attached via an amide bond to the alpha-amino group of an N-terminal amino acid of a nascent polypeptide...
in their N-terminal region, which contributes to their membrane association.
Human proteins containing this domain
ARF1ARF1
ADP-ribosylation factor 1 is a protein that in humans is encoded by the ARF1 gene.-Interactions:ARF1 has been shown to interact with GGA3, PLD2, COPB1 and Muscarinic acetylcholine receptor M3.-Further reading:...
; ARF3
ARF3
ADP-ribosylation factor 3 is a protein that in humans is encoded by the ARF3 gene.-Interactions:ARF3 has been shown to interact with ARFIP2, GGA3, GGA1, ARFIP1 and KIF23.-Further reading:...
; ARF4
ARF4
ADP-ribosylation factor 4 is a protein that in humans is encoded by the ARF4 gene.-Interactions:ARF4 has been shown to interact with Epidermal growth factor receptor.-Further reading:...
; ARF5
ARF5
ADP-ribosylation factor 5 is a protein that in humans is encoded by the ARF5 gene.-Further reading:...
; ARF6
Arf6
ADP-ribosylation factor 6 is a member of the ADP ribosylation factor family of GTP-binding proteins. ARF6 has a variety of cellular functions that are frequently involved in trafficking of biological membranes and transmembrane protein cargo...
; ARFRP1
ARFRP1
ADP-ribosylation factor-related protein 1 is a protein that in humans is encoded by the ARFRP1 gene.-Further reading:...
; ARL1
ARL1
ADP-ribosylation factor-like protein 1 is a protein that in humans is encoded by the ARL1 gene.-Interactions:ARL1 has been shown to interact with GOLGA4 and GOLGA1.-Further reading:...
; ARL10;
ARL11
ARL11
ADP-ribosylation factor-like protein 11 is a protein that in humans is encoded by the ARL11 gene.-Further reading:...
; ARL13A; ARL13B
ARL13B
ADP-ribosylation factor-like protein 13B , also known as ADP-ribosylation factor-like protein 2-like 1, is a protein that in humans is encoded by the ARL13B gene.- Function :...
; ARL14; ARL15; ARL16; ARL17; ARL2
ARL2
ADP-ribosylation factor-like protein 2 is a protein that in humans is encoded by the ARL2 gene.-Interactions:ARL2 has been shown to interact with Protein unc-119 homolog, TBCD and PDE6D.-Further reading:...
;
ARL2L1; ARL3
ARL3
ADP-ribosylation factor-like protein 3 is a protein that in humans is encoded by the ARL3 gene.-Interactions:ARL3 has been shown to interact with Protein unc-119 homolog.-Further reading:...
; ARL4A
ARL4A
ADP-ribosylation factor-like protein 4A is a protein that in humans is encoded by the ARL4A gene.-Interactions:ARL4A has been shown to interact with Karyopherin alpha 2.-Further reading:...
; ARL4C; ARL4D
ARL4D
ADP-ribosylation factor-like protein 4D is a protein that in humans is encoded by the ARL4D gene.-Further reading:...
; ARL5; ARL5A; ARL5B;
ARL6
ARL6
ADP-ribosylation factor-like protein 6 is a protein that in humans is encoded by the ARL6 gene.-External Links:* -Further reading:...
; ARL7; ARL8A
ARL8A
ADP-ribosylation factor-like protein 8A is a protein that in humans is encoded by the ARL8A gene.-Further reading:...
; ARL8B
ARL8B
ADP-ribosylation factor-like protein 8B is a protein that in humans is encoded by the ARL8B gene.-Further reading:...
; ARL9; MGC57346; SAR1A; SAR1B
SAR1B
SAR1 gene homolog B , also known as SAR1B, is a protein which in humans is encoded by the SAR1B gene.- Function :SAR1B belongs to the Sar1-ADP ribosylation factor family of small GTPases, which govern the intracellular trafficking of proteins in coat protein -coated vesicles.- Clinical significance...
;
SAR1P3; SARA1; TRIM23
TRIM23
GTP-binding protein ARD-1 is a protein that in humans is encoded by the TRIM23 gene.-Interactions:TRIM23 has been shown to interact with TRIM31, TRIM29 and PSCD1.-Further reading:...
;
Further reading
- [1]. Structure of the human ADP-ribosylation factor 1 complexed with GDP. Amor JC, Harrison DH, Kahn RA, Ringe D; Nature 1994;372:704-708.
- [2]. Structure and function of ARF proteins: Activators of cholera toxin and critical components of intracellular vesicular transport processes. Moss J, Vaughan M; J. Biol. Chem. 1995;270:12327-12330.
- [3]. Arf proteins: the membrane traffic police? Boman AL, Kahn RA; Trends Biochem Sci 1995;20:147-150.
- [4]. Human ADP-ribosylation factors. A functionally conserved family of GTP-binding proteins. Kahn RA, Kern FG, Clark J, Gelmann EP, Rulka C; J Biol Chem 1991;266:2606-2614.