Rab (G-protein)

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The Rab family of proteins is a member of the Ras superfamily of small G proteins. [1] Approximately 70 types of Rabs have now been identified in humans. [2] Rab proteins generally possess a GTPase fold, which consists of a six-stranded beta sheet which is flanked by five alpha helices. [3] Rab GTPases regulate many steps of membrane trafficking, including vesicle formation, vesicle movement along actin and tubulin networks, and membrane fusion. These processes make up the route through which cell surface proteins are trafficked from the Golgi to the plasma membrane and are recycled. Surface protein recycling returns proteins to the surface whose function involves carrying another protein or substance inside the cell, such as the transferrin receptor, or serves as a means of regulating the number of a certain type of protein molecules on the surface.

Contents

Function

The four steps of Rab protein vesicle transport (listed in text) RAB protein vesicle transport.jpg
The four steps of Rab protein vesicle transport (listed in text)

Rab proteins are peripheral membrane proteins, anchored to a membrane via a lipid group covalently linked to an amino acid. Specifically, Rabs are anchored via prenyl groups on two cysteines in the C-terminus. Rab escort proteins (REPs) deliver newly synthesized and prenylated Rab to its destination membrane by binding the hydrophobic, insoluble prenyl groups and carrying Rab through the cytoplasm. The lipid prenyl groups can then insert into the membrane, anchoring Rab at the cytoplasmic face of a vesicle or the plasma membrane. Because Rab proteins are anchored to the membrane through a flexible C-terminal region, they can be thought of as a 'balloon on a string'.

Rabs switch between two conformations, an inactive form bound to GDP (guanosine diphosphate), and an active form bound to GTP (guanosine triphosphate). A guanine nucleotide exchange factor (GEF) catalyzes the conversion from GDP-bound to GTP-bound form, thereby activating the Rab. The inherent GTP hydrolysis of Rabs can be enhanced by a GTPase-activating protein (GAP) leading to Rab inactivation. REPs carry only the GDP-bound form of Rab, and Rab effectors, proteins with which Rab interacts and through which it functions, only bind the GTP-bound form of Rab. Rab effectors are very heterogeneous, and each Rab isoform has many effectors through which it carries out multiple functions. The specific binding of the effector to the Rab protein allows the Rab protein to be effective, and conversely, the conformation shift of the Rab protein to the inactive state leads to effector dissociation from the Rab protein. [4]

Effector proteins have one of four different functions.

  1. Cargo budding, selection, and coating
  2. Vesicle transport
  3. Vesicle uncoating and tethering
  4. Vesicle fusion [4]

After membrane fusion and effector dissociation, Rab is recycled back to its membrane of origin. A GDP dissociation inhibitor (GDI) binds the prenyl groups of the inactive, GDP-bound form of Rab, inhibits the exchange of GDP for GTP (which would reactivate the Rab) and delivers Rab to its original membrane.

Clinical significance

Rab proteins and their functions are essential to proper organelle function, and as such, when any deviation is introduced to the Rab protein cycle, physiological disease states ensue. [5]

Choroideremia

Choroideremia is caused by a loss-of-function mutation in the CHM gene which codes for Rab escort protein (REP-1). REP-1 and REP-2 (a REP-1 like protein) both help with the prenylation and transport of Rab proteins. [6] Rab27 has been found to preferentially depend on REP-1 for prenylation, which could be the underlying cause of choroideremia. [7]

Intellectual disability

Mutations in the GDI1 gene, which encodes a guanosine nucleotide dissociation inhibitor, have been shown to lead to X-linked nonspecific intellectual disability. In a study done on mice, carriers for a deletion of the GDI1 gene have shown marked abnormalities in short-term memory formation and social interaction patterns. It is noted that the social and behavioral patterns exhibited in mice that are carriers of the GDI1 protein are similar to those observed in humans with the same deletion. The loss of the GDI1 gene has been shown through brain extracts of the mutant mice to lead to the accumulation of the Rab4 and Rab5 proteins, thus inhibiting their function. [4]

Cancer/carcinogenesis

Evidence shows that overexpression of Rab GTPases have a striking relationship with carcinogenesis, such as in prostate cancer. [8] [9] There are many mechanisms by which Rab protein dysfunction has been shown to cause cancer. To name a few, elevated expression of the oncogenic Rab1, along with Rab1A proteins, promote the growth of tumors, often with a poor prognosis. The overexpression of Rab23 has been linked to gastric cancer. In addition to directly causing cancer, dysregulation of Rab proteins has also been linked to progression of already existent tumors, and contributing to their malignancy. [5]

Parkinson's disease

Mutations of the Rab39b protein have been linked to X-linked intellectual disability and also to a rare form of Parkinson's disease. [10]

Types of Rab proteins

There are approximately 70 different Rabs that have been identified in humans thus far. [2] They are mostly involved in vesicle trafficking. Their complexity can be understood if thought of as address labels for vesicle trafficking, defining the identity and routing of vesicles. Shown in parentheses are the equivalent names in the model organisms Saccharomyces cerevisiae [11] and Aspergillus nidulans. [12]

NameSubcellular location
RAB1 (Ypt1, RabO)Golgi complex
RAB2A ER, cis-Golgi network
RAB2B
RAB3A Secretory and synaptic vesicles
RAB3B
RAB4A Recycling endosomes
RAB4B
RAB5A Clathrin-coated vesicles, plasma membranes
RAB5C (Vps21, RabB)Early endosomes
RAB6A (Ypt6, RabC)Golgi and trans-Golgi network
RAB6B
RAB6C
RAB6D
RAB7 (Ypt7, RabS)Late endosomes, vacuoles
RAB8A Basolateral secretory vesicles
RAB8B
RAB9A Late endosome, trans-golgi network
RAB9B
RAB11A (Ypt31, RabE)Recycling endosomes, post-Golgi exocytic carriers
RAB13 Golgi, endosome, cytosol, plasma membrane
RAB14 Early endosomes
RAB17 Endosome
RAB18 Lipid droplets, golgi, endoplasmic reticulum
RAB20 Golgi, mitochondria, early phagosome, early endosome
RAB23 Plasma membrane
RAB25 Small-scale transport, promoter for tumor development [13]
RAB27 Extracellular vesicles, endosome
RAB29 Recruits LRRK2 to TGN
RAB39A Binds Caspase-1 in inflammasome

Other Rab proteins

Related Research Articles

GTPases are a large family of hydrolase enzymes that bind to the nucleotide guanosine triphosphate (GTP) and hydrolyze it to guanosine diphosphate (GDP). The GTP binding and hydrolysis takes place in the highly conserved P-loop "G domain", a protein domain common to many GTPases.

<span class="mw-page-title-main">Ras GTPase</span> GTP-binding proteins functioning on cell-cycle regulation

Ras, from "Rat sarcoma virus", is a family of related proteins that are expressed in all animal cell lineages and organs. All Ras protein family members belong to a class of protein called small GTPase, and are involved in transmitting signals within cells. Ras is the prototypical member of the Ras superfamily of proteins, which are all related in three-dimensional structure and regulate diverse cell behaviours.

Small GTPases, also known as small G-proteins, are a family of hydrolase enzymes that can bind and hydrolyze guanosine triphosphate (GTP). They are a type of G-protein found in the cytosol that are homologous to the alpha subunit of heterotrimeric G-proteins, but unlike the alpha subunit of G proteins, a small GTPase can function independently as a hydrolase enzyme to bind to and hydrolyze a guanosine triphosphate (GTP) to form guanosine diphosphate (GDP). The best-known members are the Ras GTPases and hence they are sometimes called Ras subfamily GTPases.

The Coat Protein Complex II, or COPII, is a group of proteins that facilitate the formation of vesicles to transport proteins from the endoplasmic reticulum to the Golgi apparatus or endoplasmic-reticulum–Golgi intermediate compartment. This process is termed anterograde transport, in contrast to the retrograde transport associated with the COPI complex. COPII is assembled in two parts: first an inner layer of Sar1, Sec23, and Sec24 forms; then the inner coat is surrounded by an outer lattice of Sec13 and Sec31.

<span class="mw-page-title-main">ADP ribosylation factor</span> Group of proteins

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 coatomer is a protein complex that coats membrane-bound transport vesicles. Two types of coatomers are known:

In cell signalling, Son of Sevenless (SOS) refers to a set of genes encoding guanine nucleotide exchange factors that act on the Ras subfamily of small GTPases.

<span class="mw-page-title-main">Guanine nucleotide exchange factor</span> Proteins which remove GDP from GTPases

Guanine nucleotide exchange factors (GEFs) are proteins or protein domains that activate monomeric GTPases by stimulating the release of guanosine diphosphate (GDP) to allow binding of guanosine triphosphate (GTP). A variety of unrelated structural domains have been shown to exhibit guanine nucleotide exchange activity. Some GEFs can activate multiple GTPases while others are specific to a single GTPase.

<span class="mw-page-title-main">Guanosine nucleotide dissociation inhibitor</span>

In molecular biology, the Guanosine dissociation inhibitors (GDIs) constitute a family of small GTPases that serve a regulatory role in vesicular membrane traffic. GDIs bind to the GDP-bound form of Rho and Rab small GTPases and not only prevent exchange, but also prevent the small GTPase from localizing at the membrane, which is their place of action. This inhibition can be removed by the action of a GDI displacement factor. GDIs also inhibit cdc42 by binding to its tail and preventing its insertion into membranes; hence it cannot trigger WASPs and cannot lead to nucleation of F-actin.

<span class="mw-page-title-main">GTP-binding protein regulators</span>

GTP-binding protein regulators regulate G proteins in several different ways. Small GTPases act as molecular switches in signaling pathways, which act to regulate functions of other proteins. They are active or 'ON' when it is bound to GTP and inactive or 'OFF' when bound to GDP. Activation and deactivation of small GTPases can be regarded as occurring in a cycle, between the GTP-bound and GDP-bound form, regulated by other regulatory proteins.

<span class="mw-page-title-main">Rab escort protein 1</span> Protein-coding gene in the species Homo sapiens

Rab escort protein 1 (REP1) also known as rab proteins geranylgeranyltransferase component A 1 is an enzyme that in humans is encoded by the CHM gene.

The Rho family of GTPases is a family of small signaling G proteins, and is a subfamily of the Ras superfamily. The members of the Rho GTPase family have been shown to regulate many aspects of intracellular actin dynamics, and are found in all eukaryotic kingdoms, including yeasts and some plants. Three members of the family have been studied in detail: Cdc42, Rac1, and RhoA. All G proteins are "molecular switches", and Rho proteins play a role in organelle development, cytoskeletal dynamics, cell movement, and other common cellular functions.

<span class="mw-page-title-main">RAB5A</span> Protein-coding gene in the species Homo sapiens

Ras-related protein Rab-5A is a protein that in humans is encoded by the RAB5A gene.

<span class="mw-page-title-main">RAB7A</span> Protein-coding gene in the species Homo sapiens

Ras-related protein Rab-7a is a protein that in humans is encoded by the RAB7A gene.

<span class="mw-page-title-main">GDI1</span> Protein-coding gene in humans

Rab GDP dissociation inhibitor alpha is a protein that in humans is encoded by the GDI1 gene.

<span class="mw-page-title-main">RAB3A</span> Protein-coding gene in the species Homo sapiens

Ras-related protein Rab-3A is a protein that in humans is encoded by the RAB3A gene. It is involved in calcium-triggered exocytosis in neurons.

<span class="mw-page-title-main">RAB1A</span> Protein-coding gene in the species Homo sapiens

Ras-related protein Rab-1A is a protein that in humans is encoded by the RAB1A gene.

<span class="mw-page-title-main">GDI2</span> Protein-coding gene in the species Homo sapiens

Rab GDP dissociation inhibitor beta is a protein that in humans is encoded by the GDI2 gene.

<span class="mw-page-title-main">RAB27A</span> Protein-coding gene in the species Homo sapiens

Ras-related protein Rab-27A is a protein that in humans is encoded by the RAB27A gene.

<span class="mw-page-title-main">RAB2B</span> Protein-coding gene in the species Homo sapiens

Ras-related protein Rab-2B is a protein that in humans is encoded by the RAB2B gene.

References

  1. ↑ Stenmark H, Olkkonen VM (2001). "The Rab GTPase family". Genome Biology. 2 (5): REVIEWS3007. doi: 10.1186/gb-2001-2-5-reviews3007 . PMC   138937 . PMID   11387043.
  2. 1 2 Seto, Shintaro; Tsujimura, Kunio; Horii, Toshinobu; Koide, Yukio (2014-01-01), Hayat, M. A. (ed.), "Chapter 10 - Mycobacterial Survival in Alveolar Macrophages as a Result of Coronin-1a Inhibition of Autophagosome Formation", Autophagy: Cancer, Other Pathologies, Inflammation, Immunity, Infection, and Aging, Amsterdam: Academic Press, pp. 161–170, doi:10.1016/b978-0-12-405877-4.00010-x, ISBN   978-0-12-405877-4 , retrieved 2020-11-19
  3. ↑ Hutagalung AH, Novick PJ (January 2011). "Role of Rab GTPases in membrane traffic and cell physiology". Physiological Reviews. 91 (1): 119–49. doi:10.1152/physrev.00059.2009. PMC   3710122 . PMID   21248164.
  4. 1 2 3 Seabra MC, Mules EH, Hume AN (January 2002). "Rab GTPases, intracellular traffic and disease". Trends in Molecular Medicine. 8 (1): 23–30. doi:10.1016/s1471-4914(01)02227-4. PMID   11796263.
  5. 1 2 Tzeng HT, Wang YC (October 2016). "Rab-mediated vesicle trafficking in cancer". Journal of Biomedical Science. 23 (1): 70. doi: 10.1186/s12929-016-0287-7 . PMC   5053131 . PMID   27716280.
  6. ↑ Cremers FP, Armstrong SA, Seabra MC, Brown MS, Goldstein JL (January 1994). "REP-2, a Rab escort protein encoded by the choroideremia-like gene". The Journal of Biological Chemistry. 269 (3): 2111–7. doi: 10.1016/S0021-9258(17)42142-9 . PMID   8294464.
  7. ↑ Seabra MC, Ho YK, Anant JS (October 13, 1995). "Deficient Geranylgeranylation of Ram/Rab27 in Choroideremia". The Journal of Biological Chemistry. 270 (41): 24420–24427. doi: 10.1074/jbc.270.41.24420 . PMID   7592656.
  8. ↑ Johnson IR, Parkinson-Lawrence EJ, Shandala T, Weigert R, Butler LM, Brooks DA (December 2014). "Altered endosome biogenesis in prostate cancer has biomarker potential". Molecular Cancer Research. 12 (12): 1851–62. doi:10.1158/1541-7786.MCR-14-0074. PMC   4757910 . PMID   25080433.
  9. ↑ Johnson IR, Parkinson-Lawrence EJ, Keegan H, Spillane CD, Barry-O'Crowley J, Watson WR, et al. (November 2015). "Endosomal gene expression: a new indicator for prostate cancer patient prognosis?". Oncotarget. 6 (35): 37919–29. doi:10.18632/oncotarget.6114. PMC   4741974 . PMID   26473288.
  10. ↑ Lesage S, Bras J, Cormier-Dequaire F, Condroyer C, Nicolas A, Darwent L, Guerreiro R, Majounie E, Federoff M, Heutink P, Wood NW, Gasser T, Hardy J, Tison F, Singleton A, Brice A (June 2015). "Loss-of-function mutations in RAB39B are associated with typical early-onset Parkinson disease". Neurology. Genetics. 1 (1): e9. doi:10.1212/NXG.0000000000000009. PMC   4821081 . PMID   27066548.
  11. ↑ "Saccharomyces Genome Database (SGD)". Yeast Genome Org. Stanford University.
  12. ↑ "Aspergillus Genome Database (AspGD)". Stanford University.
  13. ↑ Kessler D, Gruen GC, Heider D, Morgner J, Reis H, Schmid KW, Jendrossek V (2012). "The action of small GTPases Rab11 and Rab25 in vesicle trafficking during cell migration". Cellular Physiology and Biochemistry. 29 (5–6): 647–56. doi: 10.1159/000295249 . PMID   22613965.
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