Prof. Richard A. Kahn discovered the GTPase ADP-ribosylation factor (ARF) as a side project supporting the Nobel prize winning work of Al Gilman on heterotrimeric G proteins and the first purification of Gs. The link between the ARF and G proteins, with the first member of each family being purified in the same lab, was a biochemical quirk; i.e., ARF is an obligate cofactor in the ADP-ribosylation of Gs by cholera toxin. Interestingly, later phylogenetic analyses revealed that G proteins emerged in evolution from the ARF superfamily. Prof. Kahn went on to identify several other members of the larger family of Arf genes, which has at least 29 members in humans, and worked to uncover cellular function and mechanism for several family members. Members of the ARF family are best known for roles in regulating membrane traffic, but they have also been found to regulate such divergent processes as folding and assembly of alpha-beta tubulin, ciliogenesis, mitochondrial fusion, cytokinesis, and other essential cell functions. Still, there is much to be learned about this ancient family of proteins and their mechanisms of regulation. In this collection, a historical perspective of the discovery of many of the ARF s is given, describing how our understanding of their functions has evolved as well as new directions towards understanding this ancient family of proteins and their fundamental roles in metazoans.
ARFs, identified in prokaryotes, are indispensable for eukaryotes, because of their role in coordinating control of the endomembranes, actin cytoskeleton dynamics, and microtubules. ARFs, along with Signal Recognition Particle Receptor beta, are the root of a phylogenetic tree that includes 4 additional families of small GTP binding proteins (Ras, Rho, Ran and Rab) as well as heterotrimeric G proteins which directly evolved from ARF. Understanding ARFs is fundamental for understanding the biology of eukaryotes. While much has been learned about the function of ARFs, preconceptions based on other GTPases that evolved from ARF have resulted in missed opportunities to understand ARF functions and the functions of other GTP binding proteins. Indeed, it might be more valuable to use ARF to establish paradigms of G protein function and then determine the function of proteins evolving from ARF to better dissect shared versus overlapping functions of GTP binding proteins. Recent work, from evolutionary biology to structural biology, has begun uncovering novel mechanisms that are important for understanding ARF and the larger G protein family including Ras, Rho, and Rab.
The goal of this collection is to provide a historical perspective, describe how diverse approaches have informed one another to achieve a greater understanding of the ARFs, and the directions now being pursued to advance the new paradigms of ARF function.
Reviews and Mini-reviews on all aspects of Arf biology and biochemistry are welcome, including, but not limited to
· The evolution of the Arf family
· Structure of Arf and Arl and their complexes
· Role of Arf and Arls in Cilia, membrane trafficking, actin cytoskeleton and microtubules
· Arf binding proteins, including GEFs, GAPs and canonical effectors
Keywords: ADP-ribosylation, G proteins, ARF family, membrane traffic
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