Ras-related protein Ral-A (RALA)

The protein contains 206 amino acids for an estimated molecular weight of 23567 Da.

 

Multifunctional GTPase involved in a variety of cellular processes including gene expression, cell migration, cell proliferation, oncogenic transformation and membrane trafficking. Accomplishes its multiple functions by interacting with distinct downstream effectors. Acts as a GTP sensor for GTP-dependent exocytosis of dense core vesicles. The RALA-exocyst complex regulates integrin-dependent membrane raft exocytosis and growth signaling (PubMed:20005108). Key regulator of LPAR1 signaling and competes with GRK2 for binding to LPAR1 thus affecting the signaling properties of the receptor. Required for anchorage-independent proliferation of transformed cells (PubMed:19306925). During mitosis, supports the stabilization and elongation of the intracellular bridge between dividing cells. Cooperates with EXOC2 to recruit other components of the exocyst to the early midbody (PubMed:18756269). During mitosis, also controls mitochondrial fission by recruiting to the mitochondrion RALBP1, which mediates the phosphorylation and activation of DNM1L by the mitotic kinase cyclin B-CDK1. (updated: June 2, 2021)

Protein identification was indicated in the following studies:

  1. Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
  2. Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
  3. Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
  4. Wilson and co-workers. (2016) Comparison of the Proteome of Adult and Cord Erythroid Cells, and Changes in the Proteome Following Reticulocyte Maturation. Mol Cell Proteomics. 15(6), 1938-1946.
  5. Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
  6. D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
  7. Chu and co-workers. (2018) Quantitative mass spectrometry of human reticulocytes reveal proteome-wide modifications during maturation. Br J Haematol. 180(1), 118-133.

Methods

The following articles were analysed to gather the proteome content of erythrocytes.

The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.

PublicationIdentification 1Uniprot mapping 2Not mapped /
Obsolete		TrEMBLSwiss-Prot
Goodman (2013)2289 (gene list)227853205992269
Lange (2014)123412347281224
Hegedus (2015)2638262202352387
Wilson (2016)165815281702911068
d'Alessandro (2017)18261817201815
Bryk (2017)20902060101081942
Chu (2018)18531804553621387

1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry

The compilation of older studies can be retrieved from the Red Blood Cell Collection database.

The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.

No sequence conservation computed yet.
Protein sequence (FASTA)
Protein coevolution profile (FreeContact)
Multiple Sequence Alignment (Muscle)

This protein is annotated as membranous in Gene Ontology, is annotated as membranous in UniProt.


Interpro domains
Total structural coverage: 100%
Model score: 100
No model available.

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The reference OMIM entry for this protein is 179550

V-ral simian leukemia viral oncogene homolog a; rala
Ras-like protein; ral

CLONING

Rousseau-Merck et al. (1988) stated that human cDNAs coding for RAL, a protein that shares about 50% homology with RAS proteins (see HRAS; 190020), had been isolated. Using a simian Rala cDNA probe and moderate hybridization stringency, Chardin and Tavitian (1989) cloned RALA and RALB (179551) from a human pheochromocytoma cDNA library. The deduced 206-amino acid RALA protein shares about 85% identity with RALB.

GENE FUNCTION

Sablina et al. (2007) found that suppression of PP2A A-beta (PPP2R1B; 603113) expression allowed immortalized human cell lines to achieve a tumorigenic state. Cancer-associated A-beta mutants failed to reverse this tumorigenic phenotype, indicating that the mutants functioned as null alleles. Cancer-derived A-beta mutants failed to form a complex with the small GTPase RALA, whereas wildtype A-beta-containing complexes dephosphorylated RALA at ser183 and ser194, inactivating RALA and abolishing its transforming function. Sablina et al. (2007) concluded that PP2A A-beta is a tumor suppressor that transforms immortalized cells by regulating RALA function. The exocyst is an evolutionarily conserved octameric complex involved in post-Golgi targeting of secretory vesicles. Moskalenko et al. (2003) noted that RAL GTPases regulate exocyst-dependent trafficking and are required for exocyst assembly. Using yeast 2-hybrid analysis of HEK293T cells, they showed that human EXO84 (EXOC8; 615283) interacted with RALA and RALB (179551), but not with any other small GTPase examined. RALA and RALB interacted with EXO84 and with SEC5 (EXOC2; 615329), but not with any other exocyst component examined. In vitro binding assays revealed that EXO84 interacted with GTP-bound RALA, and truncation analysis revealed that the pleckstrin (PLEK; 173570) homology (PH) domain of EXO84 was required for the interaction. Membrane depolarization resulted in recruitment of the isolated RAL-binding domain of EXO84 to membranes, and this recruitment required lipid-binding prenylated RALB. RAL-GTP competed with phosphatidylinositol 3,4,5-trisphosphate for EXO84 binding. In rat PC12 cells, Exo84 appeared to fractionate with a subcomplex of vesicles that included Sec10 (EXOC5; 604469), but not Sec5. Moskalenko et al. (2003) proposed that RAL GTPases regulate assembly of the full exocyst complex through interaction with EXO84 and SEC5. Equal distribution of mitochondria to daughter cells during mitosis requires fission, which depends on recruitment of the large GTPase DRP1 (DNM1L; 603850) to the outer mitochondrial membrane and phosphorylation of DRP1 by cyclin B (CCNB1; 123836)-CDK1 (116940). Using M-phase HeLa cells, Kashatus et al. (2011) found that the mitotic kinase Aurora A (AURKA; 603072) phosphorylated RALA at ser194, resulting in redistribution of RALA to mitochondria, where it recruited RALBP1 (605801) and DRP1. Subsequently, RALBP1 induced cyclin B-CDK1-dependent phosphorylation of DRP1. Knockdown of RALBP1, but not RALA, decreased the amount of phosphorylated DRP1. Knockdown of either RALA or RALBP1 blocked mitochondrial fission, causing unequal partitioning of mitochondria between daughter cells, reduced cellular content of ATP, and decreased numbers of metabolically active cells. Kashatus et al. (2011) concluded that the mitotic kinases Aurora A and cyclin B-CDK1 converge on RALA and RALBP1 to promote mitochondrial fission and appropriate distribution of mitochondria to daughter cells.

MAPPING

Rousseau-M ... More on the omim web site

Subscribe to this protein entry history

July 1, 2021: Protein entry updated
Automatic update: Entry updated from uniprot information.

Feb. 10, 2018: Protein entry updated
Automatic update: Entry updated from uniprot information.

Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated

Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated

March 16, 2016: Protein entry updated
Automatic update: OMIM entry 179550 was added.