View source for ADP ribosylation factor

{{Short description|Group of proteins}}
{{about|a small GTP-binding protein|p14ARF tumor suppressor gene|p14arf}}

{{Pfam box
| Symbol = Arf
| Name = 
| image =1ksg_opm.png
| width =250
| caption =Membrane-bound ADP ribosylation factor-like protein 2 ([[ARL2]] mouse, red), complex with [[phosphodiesterase]] delta (yellow) ({{PDB3|1ksg}}) Blue dots show hydrocarbon boundary of the [[lipid bilayer]] 
| Pfam= PF00025
| InterPro= IPR006689
| SMART=  ARF
| PROSITE = PDOC01020
| SCOP = 1hur
| TCDB =
| CDD = cd00878
| OPM family= 124
| OPM protein= 1ksg
| Membranome family = 1103
}}
[[File:ADP ribosylation factor localization in the Golgi apparatus of a living macrophage.png|thumb|250px|Distribution of ARF in a living [[macrophage]], highlighting the [[Golgi apparatus]].]]
'''ADP ribosylation factors''' ('''ARFs''') are members of the ARF family of [[GTP-binding protein]]s 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 [[vesicle (biology)|vesicular]] traffic and [[actin]] remodelling.

The small ADP ribosylation factor (Arf) GTP-binding proteins are major regulators of vesicle biogenesis in intracellular traffic.<ref name="PUB00009830">{{Cite journal 
|vauthors=Pasqualato S, Renault L, Cherfils J | doi = 10.1093/embo-reports/kvf221 
| title = Arf, Arl, Arp and Sar proteins: A family of GTP-binding proteins with a structural device for 'front-back' communication 
| journal = EMBO Reports 
| volume = 3 
| issue = 11 
| pages = 1035–1041 
| year = 2002 
| pmid = 12429613 
| pmc =1307594 
}}</ref> 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. ARFs act as a regulatory subunit that control coat assembly in coat protein I ([[COPI]]), and [[clathrin-coated vesicle]]s.{{citation needed|date=July 2023}}

===GTP/GDP exchange proteins===
ARF binds to two forms of the guanosine nucleotide, [[guanosine triphosphate]] (GTP) and [[guanosine diphosphate]] (GDP). The shape of the ARF molecule is dependent upon the form to which it is bound, 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 [[hydrolysis|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.

===Other proteins===
Other proteins interact with ARF, depending upon whether or not it is bound to GTP or GDP. The active form, ARF*GTP, binds to vesicle coat proteins and adaptors, including coat protein I (COPI) and various phospholipids. The inactive form is only known to bind to a class of transmembrane proteins.
Different types of ARF bind specifically different kinds of effector proteins.

==Phylogeny==

There are currently 6 known mammalian ARF proteins, which are divided into three classes of ARFs:

* class 1: {{Gene|ARF1}}, {{Gene|ARF2}}, {{Gene|ARF3}}
* class 2: {{Gene|ARF4}}, {{Gene|ARF5}}
* class 3: {{Gene|ARF6}}. (See also [[arf6|ARF6]])

==Structure==
ARFs are small proteins of approximately 20 [[kilodalton|kDa]] in size.  They contain two switch regions, which change relative positions between cycles of GDP/GTP-binding.  ARFs are frequently [[Myristoylation|myristoylated]] in their N-terminal region, which contributes to their membrane association.

== Examples ==

Human genes encoding proteins containing this domain include:
* [[ARF1]] [[ARF3]] [[ARF4]] [[ARF5]] [[ARF6]] [[ARFRP1]]
* [[ARL1]] [[ARL2]] [[ARL2L1]] [[ARL3]] [[ARL4A]] [[ARL4C]] [[ARL4D]] [[ARL5]] [[ARL5A]] [[ARL5B]]
* [[ARL10]] [[ARL11]] [[ARL13A]] [[ARL13B]] [[ARL14]] [[ARL15]] [[ARL16]] [[ARL17]] 
* [[ARL6]] [[ARL7]] [[ARL8A]] [[ARL8B]] [[ARL9]]
* [[MGC57346]]
* [[SAR1A]] [[SAR1B]] [[SAR1P3]] [[SARA1]] [[TRIM23]]

==See also==
* [[Brefeldin A]]

==References==
{{Reflist}}

==Further reading==
{{refbegin}}
* {{Cite journal 
|vauthors=Donaldson JG, Honda A | doi = 10.1042/BST0330639 
| title = Localization and function of Arf family GTPases 
| journal = Biochemical Society Transactions 
| volume = 33 
| issue = 4 
| pages = 639–642 
| year = 2005 
| pmid = 16042562 
| pmc = 
}}
* {{Cite journal
| title = Arf and its many interactors 
| journal = Current Opinion in Cell Biology 
| volume = 15 
| issue = 4 
| pages = 396–404 
| year = 2003 
| pmid = 12892779
|doi=10.1016/S0955-0674(03)00071-1
|vauthors=Nie Z, Hirsch DS, Randazzo PA }}
* {{Cite journal 
|vauthors=Amor JC, Harrison DH, Kahn RA, Ringe D | title = Structure of the human ADP-ribosylation factor 1 complexed with GDP 
| doi = 10.1038/372704a0 
| journal = Nature 
| volume = 372 
| issue = 6507 
| pages = 704–708 
| year = 1994 
| pmid = 7990966 
| pmc = 
| bibcode = 1994Natur.372..704C 
| s2cid = 4362056 
}}
* {{Cite journal 
| author = Moss J, Vaughan M
| title = Structure and function of ARF proteins: Activators of cholera toxin and critical components of intracellular vesicular transport processes 
| journal = The Journal of Biological Chemistry 
| volume = 270 
| issue = 21 
| pages = 12327–12330 
| year = 1995 
| pmid = 7759471
| doi=10.1074/jbc.270.21.12327
| last2 = Vaughan 
| doi-access = free 
}}
* {{Cite journal 
| author = Boman AL, Kahn RA
| title = Arf proteins: The membrane traffic police? 
| journal = Trends in Biochemical Sciences 
| volume = 20 
| issue = 4 
| pages = 147–150 
| year = 1995 
| pmid = 7770914
| doi=10.1016/s0968-0004(00)88991-4
| last2 = Kahn 
}}
* {{Cite journal 
|vauthors=Kahn RA, Kern FG, Clark J, Gelmann EP, Rulka C | title = Human ADP-ribosylation factors. A functionally conserved family of GTP-binding proteins 
| journal = The Journal of Biological Chemistry 
| volume = 266 
| issue = 4 
| pages = 2606–2614 
| year = 1991 
| doi = 10.1016/S0021-9258(18)52288-2 
| pmid = 1899243
| doi-access = free 
}}
{{refend}}

==External links==
* {{ELM|TRG_Cilium_Arf4_1}}

{{GTPases}}
{{Vesicular transport proteins}}
{{Intracellular signaling peptides and proteins}}
{{InterPro content|IPR006689}}

{{DEFAULTSORT:Adp Ribosylation Factor}}
[[Category:Protein domains]]
[[Category:Peripheral membrane proteins]]