RAB11B

Function

Members of the Rab11 subfamily act in recycling of proteins from the endosomes to the plasma membrane, in transport of molecules from the trans-Golgi network to the plasma membrane and in phagocytosis. This subfamily also acts in polarized transport in epithelial cells. Whereas most studies refer to the Rab11a isoform, little is known about Rab11b so far. Rab11b localizes predominantly in the pericentriolar recycling compartment and serves as an important component of the vesicular machinery. It is required for the transfer of internalized transferrin from the recycling compartment to the plasma membrane for which active Rab11b as well as GTP hydrolysis is necessary.

Structure

All Ras GTPases consist of a similar core structure and highly conserved P-loop, switch 1 and switch 2 regions. The Rab11b monomer exhibits a typical Ras-like, small GTPase fold with a six stranded β-sheet core (β1-β6) surrounded by five major α-helices (α1-α5) and one minor α-helix (α6). According to the sequence similarity to other Rab GTPases can be assumed that they show closely resembling characteristics in nucleotide binding and hydrolysis. However, Rab11 isoforms could differ in hydrolysis kinetics owing to the differences in conformation, since Rab11a and Rab11b do not show an α-helical switch 2 region like other Rab GTPases. Rab11b shares 90% amino acid identity to Rab11a. Kinetic experiments with Rab11a/b and Rab11-interacting proteins (FIPs) indicate that FIPs cannot differentiate between GTP-bound Rab11a and Rab11b in vitro. The major divergence reveals in the inactive state. While Pasqualato et al. crystallized inactive Rab11a as a dimer in the asymmetric unit, Scapin et al. observed single crystallographically independent monomers of both the GDP- and the GppNHp-bound Rab11b structures.

Clinical significance

Due to their crucial importance in vesicle transport and recycling, Rab11 proteins are linked to various non-pathogen or pathogen induced diseases. Most of the published data do not specify whether it is the a- or the b-isoform. Rab11 proteins have been implicated in Alzheimer's disease, Arthrogryposis-renal dysfunction-cholestasis (ARC), Batten disease, and Charcot-Marie-Tooth Neuropathy Type 4C (CMT4C). Intracellular bacteria Chlamydia pneumoniae and Chlamydia trachomatis that replicate in membrane bound compartments hijack the trafficking machinery recruiting Rab GTPases to promote their replication within the host cell. Knock down of Rab11 decreased the formation of infectious particles. Recent studies report a similar use of intracellular trafficking by Hantavirus and Influenza A virus. Replicated viruses benefit from Rab11 mediated recycling endosome pathway to exit the cell and infect surrounding tissue.

References

References

1. (Dec 1994). "Molecular cloning of two small GTP-binding proteins from human skeletal muscle". Biochemical and Biophysical Research Communications.
2. "Entrez Gene: RAB11B RAB11B, member RAS oncogene family".
3. (Mar 2000). "Genomic structure of murine Rab11 family members". Biochemical and Biophysical Research Communications.
4. (Jun 1998). "Human rab11a: transcription, chromosome mapping and effect on the expression levels of host GTP-binding proteins". FEBS Letters.
5. (Dec 2000). "Rab11 regulates the compartmentalization of early endosomes required for efficient transport from early endosomes to the trans-golgi network". The Journal of Cell Biology.
6. (Aug 1994). "Molecular analysis of mouse Rab11b: a new type of mammalian YPT/Rab protein". Genomics.
7. (Dec 1996). "Two GTPase isoforms, Ypt31p and Ypt32p, are essential for Golgi function in yeast". The EMBO Journal.
8. (May 1997). "Two new Ypt GTPases are required for exit from the yeast trans-Golgi compartment". The Journal of Cell Biology.
9. (Nov 2003). "Rab11b resides in a vesicular compartment distinct from Rab11a in parietal cells and other epithelial cells". Experimental Cell Research.
10. (Nov 1998). "Rab11 is required for trans-golgi network-to-plasma membrane transport and a preferential target for GDP dissociation inhibitor". Molecular Biology of the Cell.
11. (Jan 2000). "A Rab11-containing rapidly recycling compartment in macrophages that promotes phagocytosis". Proceedings of the National Academy of Sciences of the United States of America.
12. (Jun 2006). "The crystal structure of the small GTPase Rab11b reveals critical differences relative to the Rab11a isoform". Journal of Structural Biology.
13. (Nov 1996). "Rab11 regulates recycling through the pericentriolar recycling endosome". The Journal of Cell Biology.
14. (Sep 2000). "Regulation of vesicle trafficking in madin-darby canine kidney cells by Rab11a and Rab25". The Journal of Biological Chemistry.
15. (Aug 2000). "Rab11b is essential for recycling of transferrin to the plasma membrane". Experimental Cell Research.
16. (Oct 2006). "Structural basis for Rab11-dependent membrane recruitment of a family of Rab11-interacting protein 3 (FIP3)/Arfophilin-1". Proceedings of the National Academy of Sciences of the United States of America.
17. (Mar 2004). "The structural GDP/GTP cycle of Rab11 reveals a novel interface involved in the dynamics of recycling endosomes". The Journal of Biological Chemistry.
18. (Apr 2002). "Estrogen lowers Alzheimer beta-amyloid generation by stimulating trans-Golgi network vesicle biogenesis". The Journal of Biological Chemistry.
19. (Jul 1999). "Presenilins interact with Rab11, a small GTPase involved in the regulation of vesicular transport". Human Molecular Genetics.
20. (Apr 2010). "Mutations in VIPAR cause an arthrogryposis, renal dysfunction and cholestasis syndrome phenotype with defects in epithelial polarization". Nature Genetics.
21. (Dec 2004). "Interconnections of CLN3, Hook1 and Rab proteins link Batten disease to defects in the endocytic pathway". Human Molecular Genetics.
22. (Aug 2010). "SH3TC2, a protein mutant in Charcot-Marie-Tooth neuropathy, links peripheral nerve myelination to endosomal recycling". Brain.
23. (Dec 2007). "Chlamydia pneumoniae inclusion membrane protein Cpn0585 interacts with multiple Rab GTPases". Infection and Immunity.
24. (Oct 2009). "Rab6 and Rab11 regulate Chlamydia trachomatis development and golgin-84-dependent Golgi fragmentation". PLOS Pathogens.
25. (Oct 2003). "Rab GTPases are recruited to chlamydial inclusions in both a species-dependent and species-independent manner". Infection and Immunity.
26. (May 2011). "A Rab11- and microtubule-dependent mechanism for cytoplasmic transport of influenza A virus viral RNA". Journal of Virology.
27. (Jun 2010). "The Rab11 pathway is required for influenza A virus budding and filament formation". Journal of Virology.
28. (2011-06-22). "Apical transport of influenza A virus ribonucleoprotein requires Rab11-positive recycling endosome". PLOS ONE.
29. Rowe, Regina K.. (2008-12-20). "Roles for the recycling endosome, Rab8, and Rab11 in hantavirus release from epithelial cells". Virology.